ABSTRACT
BACKGROUND: Genetic variants involving the MED13L gene can lead to an autosomal dominant syndrome characterised by intellectual disability/developmental delay and facial dysmorphism. METHODS: We investigated two cases (one familial and one isolated) of intellectual disability with speech delay and dysmorphic facial features by whole-exome sequencing analyses. Further, we performed a literature review about clinical and molecular aspects of MED13L gene and syndrome. RESULTS: Two MED13L variants have been identified [MED13L(NM_015335.5):c.4417C>T and MED13L(NM_015335.5):c.2318delC] and were classified as pathogenic according to the ACMG (American College of Medical Genetics and Genomics) guidelines. One of the variants was present in sibs. CONCLUSIONS: The two pathogenic variants identified have not been previously reported. Importantly, this is the first report of a familial case of MED13L nonsense mutation. Although the parents of the affected children were no longer available for analysis, their apparently normal phenotypes were surmised from familial verbal descriptions corresponding to normal mental behaviour and phenotype. In this situation, the familial component of mutation transmission might be caused by gonadal mosaicism of a MED13L mutation in a gonad from either the father or the mother. The case reports and the literature review presented in this manuscript can be useful for genetic counselling.
Subject(s)
Intellectual Disability , Mediator Complex , Humans , Intellectual Disability/genetics , Mediator Complex/genetics , PhenotypeABSTRACT
Evaluation of expression profile in autism spectrum disorder (ASD) patients is an important approach to understand possible similar functional consequences that may underlie disease pathophysiology regardless of its genetic heterogeneity. Induced pluripotent stem cell (iPSC)-derived neuronal models have been useful to explore this question, but larger cohorts and different ASD endophenotypes still need to be investigated. Moreover, whether changes seen in this in vitro model reflect previous findings in ASD postmortem brains and how consistent they are across the studies remain underexplored questions. We examined the transcriptome of iPSC-derived neuronal cells from a normocephalic ASD cohort composed mostly of high-functioning individuals and from non-ASD individuals. ASD patients presented expression dysregulation of a module of co-expressed genes involved in protein synthesis in neuronal progenitor cells (NPC), and a module of genes related to synapse/neurotransmission and a module related to translation in neurons. Proteomic analysis in NPC revealed potential molecular links between the modules dysregulated in NPC and in neurons. Remarkably, the comparison of our results to a series of transcriptome studies revealed that the module related to synapse has been consistently found as upregulated in iPSC-derived neurons-which has an expression profile more closely related to fetal brain-while downregulated in postmortem brain tissue, indicating a reliable association of this network to the disease and suggesting that its dysregulation might occur in different directions across development in ASD individuals. Therefore, the expression pattern of this network might be used as biomarker for ASD and should be experimentally explored as a therapeutic target.
Subject(s)
Autism Spectrum Disorder , Induced Pluripotent Stem Cells , Autism Spectrum Disorder/genetics , Humans , Neurons , Proteomics , Transcriptome/geneticsABSTRACT
BACKGROUND: Recent data associate eosinophilic esophagitis (EoE) with IgG4 rather than IgE, but its significance and function have not been determined. Our aims were to measure esophageal IgG4 levels and to determine functional correlations as assessed by histologic and transcriptome analyses. METHODS: This case-control study included pediatric subjects with EoE (≥15 eosinophils/HPF) and non-EoE controls. Protein lysates were analyzed for IgA, IgM, and IgG1-IgG4 using the Luminex 100 system; IgE was quantified by ELISA. Esophageal biopsies were scored using the EoE histology scoring system. Transcripts were probed by the EoE diagnostic panel, designed to examine the expression of 96 esophageal transcripts. RESULTS: Esophageal IgG subclasses, IgA, and IgM, but not IgE, were increased in subjects with EoE relative to controls. The greatest change between groups was seen in IgG4 (4.2 mg/g protein [interquartile range: 1.0-13.1 mg/g protein] vs 0.2 mg/g protein [0.1-0.9]; P < .0001). Tissue IgG4 levels correlated with esophageal eosinophil counts (P = .0006); histologic grade (P = .0011) and stage (P = .0112) scores; and IL4, IL10, IL13, but not TGFB1, expression and had strong associations with a subset of the EoE transcriptome. Esophageal IgG4 transcript expression was increased and correlated with IgG4 protein levels and IL10 expression. CONCLUSION: These findings extend prior studies on IgG4 in adult EoE to the pediatric population and provide deeper understanding of the potential significance and regulation of IgG4, demonstrating that IgG4 is a relevant feature of the disease; is closely related to esophageal eosinophil levels, type 2 immunity and T regulatory cytokines; and is likely produced locally.
Subject(s)
Eosinophilic Esophagitis/diagnosis , Eosinophilic Esophagitis/etiology , Immunoglobulin G/immunology , Transcriptome , Biopsy , Case-Control Studies , Child , Child, Preschool , Esophageal Mucosa/immunology , Esophageal Mucosa/metabolism , Esophageal Mucosa/pathology , Esophagus/immunology , Esophagus/metabolism , Esophagus/pathology , Female , Gene Expression , Histocytochemistry , Humans , Immunoglobulin G/genetics , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Isotypes/immunology , MaleABSTRACT
We compared the prevalence of self-injurious behaviors (SIB) in preschoolers aged 30-68 months with autism spectrum disorder (ASD) (n = 691) versus other developmental delays and disorders (DD) (n = 977) accounting for sociodemographic, cognitive, and medical factors. SIB prevalence was higher in ASD versus all DD [adjusted odds-ratio (aOR) 2.13 (95% confidence interval (95% CI) 1.53, 2.97)]. In subgroup analyses, SIB prevalence was higher in ASD versus DD without ASD symptoms [aOR 4.42 (95% CI 2.66, 7.33)], but was similar between ASD and DD with ASD symptoms [aOR 1.09 (95% CI 0.68, 1.77)]. We confirmed higher prevalence of SIB in ASD versus DD, independent of confounders. In children with DD, SIB prevalence increased with more ASD symptoms. These findings are informative to clinicians, researchers, and policymakers.
Subject(s)
Autism Spectrum Disorder/complications , Developmental Disabilities/complications , Self-Injurious Behavior/epidemiology , Child, Preschool , Female , Humans , Male , PrevalenceABSTRACT
In this study, we explored potential associations among self-injurious behaviors (SIB) and a diverse group of protective and risk factors in children with autism spectrum disorder from two databases: Autism and Developmental Disabilities Monitoring (ADDM) Network and the Autism Speaks-Autism Treatment Network (AS-ATN). The presence of SIB was determined from children's records in ADDM and a parent questionnaire in AS-ATN. We used multiple imputation to account for missing data and a non-linear mixed model with site as a random effect to test for associations. Despite differences between the two databases, similar associations were found; SIB were associated with developmental, behavioral, and somatic factors. Implications of these findings are discussed in relation to possible etiology, future longitudinal studies, and clinical practice.
Subject(s)
Autism Spectrum Disorder/epidemiology , Self-Injurious Behavior/epidemiology , Child , Comorbidity , Cross-Sectional Studies , Databases, Factual , Female , Humans , Male , Protective Factors , Risk Factors , United States/epidemiologyABSTRACT
BACKGROUND: Wilms tumor (WT) has a not completely elucidated pathogenesis. DNA copy number alterations (CNAs) are common in cancer, and often define key pathogenic events. The aim of this work was to investigate CNAs in order to disclose new candidate genes for Wilms tumorigenesis. RESULTS: Array-CGH of 50 primary WTs without pre-chemotherapy revealed a few recurrent CNAs not previously reported, such as 7q and 20q gains, and 7p loss. Genomic amplifications were exclusively detected in 3 cases of WTs that later relapsed, which also exhibited an increased frequency of gains affecting a 16.2 Mb 1q21.1-q23.2 region, losses at 11p, 11q distal, and 16q, and WT1 deletions. Conversely, aneuploidies of chromosomes 13 and 19 were found only in WTs without further relapse. The 1q21.1-q23.2 gain associated with WT relapse harbours genes such as CHD1L, CRABP2, GJA8, MEX3A and MLLT11 that were found to be over-expressed in WTs. In addition, down-regulation of genes encompassed by focal deletions highlighted new potential tumor suppressors such as CNKSR1, MAN1C1, PAQR7 (1p36), TWIST1, SOSTDC1 (7p14.1-p12.2), BBOX and FIBIN (11p13), and PLCG2 (16q). CONCLUSION: This study confirmed the presence of CNAs previously related to WT and characterized new CNAs found only in few cases. The later were found in higher frequency in relapsed cases, suggesting that they could be associated with WT progression.
ABSTRACT
Genetic heterogeneity has made the identification of genes related to hearing impairment a challenge. In the absence of a clear phenotypic aetiology, recurrence risk estimates are often based on family segregation and may be imprecise. We profiled by oligonucleotide array-CGH patients presenting non-syndromic hearing loss with presumptive autosomal recessive (n = 50) or autosomal dominant (n = 50) patterns of inheritance. Rare copy number variants (CNVs) were detected in 12 probands; four of the detected CNVs comprised genes previously associated with hearing loss (POU4F3, EYA4, USH2A, and BCAP31) and were considered causative, stressing the contribution of genomic imbalance to non-syndromic deafness. In six cases, segregation of the CNVs in pedigrees excluded them as causative. In one case, segregation could not be investigated, while in another case, a point mutation likely explains the phenotype. These findings show that the presumptive patterns of inheritance were incorrect in at least two cases, thereby impacting genetic counselling. In addition, we report the first duplication reciprocal to the rare ABCD1, BCAP31, and SLC6A8 contiguous deletion syndrome; as with most microduplication syndromes, the associated phenotype is much milder than the respective microdeletion and, in this case, was restricted to hearing impairment.
ABSTRACT
We report on a patient carrying a 17q21.31 microdeletion and exhibiting many common syndrome features, together with other clinical signs which have rarely or never been described to date. The detected 695-kb 17q21.31 deletion is larger than in most previously reported cases but is still probably the result of recombination between flanking low-copy repeats. Due to the complexity of the patient's clinical condition, together with the presence of 3 previously unreported symptoms, namely chronic anemia, cervical vertebrae arthrosis and vertebrae fusion, this case is an important addition to the existing knowledge about the 17q21.31 microdeletion syndrome.
ABSTRACT
Injuries of the knees are common. The Ottawa knee rule provides decisional support to determine whether radiographs are indicated or not. With the use of ultrasound it is possible to detect defects of the extensor ligaments and the anterior cruciate ligament. Furthermore, it is possible to detect indirect signs of an intra-articular fracture, e.g. lipohemarthrosis. In complex fractures, e.g. tibial plateau fractures, further diagnostic procedures with multislice computed tomography (CT) are needed for accurate classification and preoperative planning. Multislice CT with CT angiography enables three-dimensional reconstruction of the knee and non-invasive vascular imaging for detection of vascular injury. Magnetic resonance imaging (MRI) is the gold standard for detection of occult fractures and injuries of the ligaments and menisci. Higher field strengths can be used to improve the diagnostics of cartilage lesions. Virtual MR arthrography is superior to conventional MRI for detection of cartilage lesions especially after meniscus surgery.
Subject(s)
Diagnostic Imaging/trends , Image Enhancement/methods , Knee Injuries/diagnosis , Knee Injuries/therapy , HumansABSTRACT
Laser ablation (LA) is momentarily the only invasive ablation procedure besides radiofrequency ablation (RFA) which can be performed entirely under magnetic resonance imaging (MRI) guidance. The long-term outcome and morbidity profiles are broadly identical for both modalities, excluding the RFA-specific prevalence for skin burns. The technical and logistic disadvantages of LA have been overcome since the introduction of miniaturized two-component applicators. The main advantage of LA is its superior MRI compatibility. Interference-free imaging during LA allows MR thermometric real-time therapy control without the need for RF filters. High-resolution thermometry in the target zone only makes sense without the extinction artifact of a metal probe and this condition is met only by the glass fibers of LA. An independent therapy monitoring is crucial in modern scenarios of oncologic quality management.
Subject(s)
Laser Therapy/trends , Magnetic Resonance Imaging/trends , Neoplasms/diagnosis , Neoplasms/surgery , Surgery, Computer-Assisted/trends , Thermography/methods , HumansABSTRACT
BACKGROUND: Congenital deletions affecting 3q11q23 have rarely been reported and only five cases have been molecularly characterised. Genotype-phenotype correlation has been hampered by the variable sizes and breakpoints of the deletions. In this study, 14 novel patients with deletions in 3q11q23 were investigated and compared with 13 previously reported patients. METHODS: Clinical data were collected from 14 novel patients that had been investigated by high resolution microarray techniques. Molecular investigation and updated clinical information of one cytogenetically previously reported patient were also included. RESULTS: The molecular investigation identified deletions in the region 3q12.3q21.3 with different boundaries and variable sizes. The smallest studied deletion was 580 kb, located in 3q13.31. Genotype-phenotype comparison in 24 patients sharing this shortest region of overlapping deletion revealed several common major characteristics including significant developmental delay, muscular hypotonia, a high arched palate, and recognisable facial features including a short philtrum and protruding lips. Abnormal genitalia were found in the majority of males, several having micropenis. Finally, a postnatal growth pattern above the mean was apparent. The 580 kb deleted region includes five RefSeq genes and two of them are strong candidate genes for the developmental delay: DRD3 and ZBTB20. CONCLUSION: A newly recognised 3q13.31 microdeletion syndrome is delineated which is of diagnostic and prognostic value. Furthermore, two genes are suggested to be responsible for the main phenotype.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 3 , Developmental Disabilities/genetics , Facies , Genitalia, Male/abnormalities , Growth Disorders/genetics , Developmental Disabilities/diagnosis , Female , Genetic Association Studies , Humans , Male , Nerve Tissue Proteins/genetics , Receptors, Dopamine D3/genetics , Syndrome , Transcription Factors/geneticsABSTRACT
The treatment of thoracic aortic diseases has undergone a paradigm shift due to the introduction and further development of interventional techniques in recent years. Thoracic endovascular aortic repair (TEVAR) of the descending aorta has significantly lower mortality and complication rates compared to open repair. Meanwhile this endovascular approach is the first option for the treatment of the majority of thoracic aortic diseases.
Subject(s)
Aortic Aneurysm, Thoracic/surgery , Aortic Dissection/surgery , Aortic Rupture/surgery , Blood Vessel Prosthesis Implantation/methods , Endovascular Procedures/methods , Adult , Aged , Aged, 80 and over , Aortic Dissection/mortality , Aortic Aneurysm, Thoracic/mortality , Aortography/methods , Contrast Media/administration & dosage , Female , Hospital Mortality , Humans , Image Processing, Computer-Assisted/methods , Imaging, Three-Dimensional/methods , Magnetic Resonance Angiography/methods , Male , Middle Aged , Postoperative Complications/etiology , Postoperative Complications/mortality , Prosthesis Design , Prosthesis Failure , Randomized Controlled Trials as Topic , Stents , Survival Rate , Young AdultABSTRACT
In teleradiology, imaging data are transferred over a distance. This service is provided for the purpose of consulting or teleradiological reading in the narrower sense. Once a justification has been proposed in the latter, the examination is performed under the responsibility of a radiologist who is not present on site. The need for teleradiology services often derives from sparsely populated areas, a shortage of doctors, or the need for cost-efficient provision of radiological examinations. The providers and recipients of teleradiology services enter into an agreement specifying conditions for data transfer. The German ionizing radiation (medical exposure) regulations demand that the teleradiologist holds radiation protection qualifications and is able to reach the examination site within 45 - 60 minutes. In Germany, teleradiology services are still limited to nights, weekends, and vacations, although the German regulations allow an expansion under certain circumstances. Efforts to fundamentally change radiology in favor of teleradiology are putting the status of a radiological medical act as well as current teaching models at risk, thereby indirectly sustaining physician shortage. Transnational teleradiology services offer the possibility of cost reduction, taking advantage of out-of-hour reading and wage fluctuation. At the same time, such services are associated with deficits in quality and availability of personnel as well as the quality of medical services. In the long-term teleradiology concepts will fundamentally change radiology. Smaller radiology units will concentrate on daily business and fast reporting. Larger units also providing academic teaching can use teleradiology networks to offer specialized readings.
Subject(s)
National Health Programs/legislation & jurisprudence , Teleradiology/legislation & jurisprudence , Data Collection/economics , Data Collection/legislation & jurisprudence , European Union , Germany , Health Services Accessibility/economics , Health Services Accessibility/legislation & jurisprudence , Humans , International Cooperation , National Health Programs/economics , Radiation Protection/economics , Radiation Protection/legislation & jurisprudence , Registries , Remote Consultation/economics , Remote Consultation/legislation & jurisprudence , Teleradiology/economicsABSTRACT
INTRODUCTION: We hypothesised that gene expression in histologically normal (HN) epithelium (NlEpi) would differ between breast cancer patients and usual-risk controls undergoing reduction mammoplasty (RM), and that gene expression in NlEpi from cancer-free prophylactic mastectomy (PM) samples from high-risk women would resemble HN gene expression. METHODS: We analysed gene expression in 73 NlEpi samples microdissected from frozen tissue. In 42 samples, we used microarrays to compare gene expression between 18 RM patients and 18 age-matched HN (9 oestrogen receptor (ER)+, 9 ER-) and 6 PM patients. Data were analysed using a Bayesian approach (BADGE), and validated with quantitative real-time PCR (qPCR) in 31 independent NlEpi samples from 8 RM, 17 HN, and 6 PM patients. RESULTS: A total of 98 probe sets (86 genes) were differentially expressed between RM and HN samples. Performing hierarchical analysis with these 98 probe sets, PM and HN samples clustered together, away from RM samples. qPCR validation of independent samples was high (84%) and uniform in RM compared with HN patients, and lower (58%), but more heterogeneous, in RM compared with PM patients. The 86 genes were implicated in many processes including transcription and the MAPK pathway. CONCLUSION: Gene expression differs between the NlEpi of breast cancer cases and controls. The profile of cancer cases can be discerned in high-risk NlEpi from cancer-free breasts. This suggests that the profile is not an effect of the tumour, but may mark increased risk and reveal the earliest genomic changes of breast cancer.
Subject(s)
Breast Neoplasms/genetics , Epithelium/metabolism , Gene Expression Profiling , Adult , Aged , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Female , Humans , Mastectomy , Middle AgedSubject(s)
Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Chromosome Deletion , Chromosomes, Human, Pair 1/genetics , Genes, Dominant/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/diagnostic imaging , Child , Child, Preschool , Chromosome Breakage , Female , Humans , Infant , Male , Radiography , SyndromeABSTRACT
The cause of hearing impairment has not been elucidated in a large proportion of patients. We screened by 1-Mb array-based comparative genomic hybridization (aCGH) 29 individuals with syndromic hearing impairment whose clinical features were not typical of known disorders. Rare chromosomal copy number changes were detected in eight patients, four de novo imbalances and four inherited from a normal parent. The de novo alterations define candidate chromosome segments likely to harbor dosage-sensitive genes related to hearing impairment, namely 1q23.3-q25.2, 2q22q23, 6p25.3 and 11q13.2-q13.4. The rare imbalances also present in normal parents might be casually associated with hearing impairment, but its role as a predisposition gene remains a possibility. Our results show that syndromic deafness is frequently associated with chromosome microimbalances (14-27%), and the use of aCGH for defining disease etiology is recommended.
Subject(s)
Chromosomal Instability/genetics , Hearing Loss/genetics , Child , Child, Preschool , Comparative Genomic Hybridization , Female , Gene Dosage , Humans , Male , SyndromeABSTRACT
Chromosome microdeletions or duplications are detected in 10-20% of patients with mental impairment and normal karyotypes. A few cases have been reported of mental impairment with microdeletions comprising tumor suppressor genes. By array-CGH we detected 4 mentally impaired individuals carrying de novo microdeletions sharing an overlapping segment of approximately 180 kb in 17p13.1. This segment encompasses 18 genes, including 3 involved in cancer, namely KCTD11/REN, DLG4/PSD95, and GPS2. Furthermore, in 2 of the patients, the deletions also included TP53, the most frequently inactivated gene in human cancers. The 3 tumor suppressor genes KCTD11, DLG4, and GPS2, in addition to the GABARAP gene, have a known or suspected function in neuronal development and are candidates for causing mental impairment in our patients. Among our 4 patients with deletions in 17p13.1, 3 were part of a Brazilian cohort of 300 mentally retarded individuals, suggesting that this segment may be particularly prone to rearrangements and appears to be an important cause (approximately 1%) of mental retardation. Further, the constitutive deletion of tumor suppressor genes in these patients, particularly TP53, probably confers a significantly increased lifetime risk for cancer and warrants careful oncological surveillance of these patients. Constitutional chromosome deletions containing tumor suppressor genes in patients with mental impairment or congenital abnormalities may represent an important mechanism linking abnormal phenotypes with increased risks of cancer.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 17/genetics , Genes, Tumor Suppressor , Intellectual Disability/genetics , Adaptor Proteins, Signal Transducing/genetics , Adolescent , Apoptosis Regulatory Proteins , Cell Cycle Proteins , Child , Child, Preschool , Chromosome Mapping , Comparative Genomic Hybridization , Disks Large Homolog 4 Protein , Female , Gene Dosage , Genes, p53 , Humans , In Situ Hybridization, Fluorescence , Intracellular Signaling Peptides and Proteins/genetics , Male , Membrane Proteins/genetics , Microtubule-Associated Proteins/genetics , Phenotype , Potassium Channels/genetics , TransferasesABSTRACT
Hemorrhagic duodenal ulcers should primarily be controlled by endoscopy. In cases of recurrent bleeding or if bleeding cannot be controlled endoscopically, open surgery is the gold standard. Rarely, atypical origin of arteries or additional atypical arteries may lead to further unexpected hemorrhagic recurrences and angiography with surgical intervention is the treatment of choice. In this article a rare case of an atypical visceral artery connecting the coeliac trunk and the gastroduodenal artery leading to recurrent bleeding from a duodenal ulcer is presented.
Subject(s)
Celiac Artery/abnormalities , Duodenal Ulcer/surgery , Duodenum/blood supply , Peptic Ulcer Hemorrhage/surgery , Stomach/blood supply , Angiography , Combined Modality Therapy , Duodenal Ulcer/diagnosis , Embolization, Therapeutic , Endoscopy, Digestive System , Humans , Injections , Male , Middle Aged , Peptic Ulcer Hemorrhage/diagnosis , Postoperative Complications/diagnosis , Postoperative Complications/surgery , Recurrence , Renin/administration & dosage , Reoperation , Shock, Hemorrhagic/diagnosis , Shock, Hemorrhagic/surgery , Surgical InstrumentsABSTRACT
AIM: This article reports on the use of magnetic resonance imaging to access the post-interventional necrosis volume of liver metastases immediately after and 48 hours after LITT. MATERIAL AND METHODS: In this prospective study, 56 liver metastases from 39 patients (16 females, 23 males, mean age 60.4 years) underwent LITT. The 56 metastases were divided into 4 groups according to the ablation strategy (dependent on multi-applicator technique and laser duration). Groups I and II were treated with an applicator and a time of ablation greater than 15 minutes and 20 minutes, respectively. In groups III and IV the multi-applicator technology with 3 or 4 applicators and a constant ablation time of 20 minutes were used. With the help of heightened contrast MRI of the liver, the portrayal of the post-interventional necrosis was conducted immediately after LITT and 48 hours after LITT. The post-interventional controls after 48 hours were performed during the inpatient stay. The protocol was complemented by an outpatient long-term control after more than 3 months. RESULTS: The local tumor control rate was initially 96.4%. After 3 months it decreased to 92.1%. The mean necrosis volume directly after LITT was: Group I (n = 11; 1 applicator, 30 watt, 10-15 minutes) 6.69 cm(3); Group II (n = 13; 1 applicator, 30 watt, 20 minutes) 10.95 cm(3); Group III (n = 28; 2 applicator, 30 watt, 10-15 minutes) 21.47 cm(3); Group IV (n = 4; 3 applicator, 30 watt, 20 minutes) 40.20 cm(3). In comparison, the necrosis volume after 48 hours increased: Group I 10.56 cm(3); Group II 15.11 cm(3); Group III 31.33 cm(3), Group IV 55.73 cm(3)). CONCLUSION: After 48 hours a progressive increase of post-interventional necrosis volumes compared to volumes directly after LITT was able to be observed. An MRI control after 48 hours, as opposed to an MRI control directly after intervention, is a better indicator for post-interventional success after LITT.
Subject(s)
Image Enhancement , Laser Therapy , Liver Neoplasms/secondary , Liver Neoplasms/surgery , Magnetic Resonance Imaging , Adult , Aged , Aged, 80 and over , Contrast Media/administration & dosage , Female , Follow-Up Studies , Humans , Liver/pathology , Liver/surgery , Liver Neoplasms/pathology , Male , Middle Aged , Necrosis , Palliative Care , Prospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation. AIM: We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome. RESULTS: We estimate the prevalence of the syndrome to be 1 in 16,000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729-41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p<10(-5)). CONCLUSION: Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.