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De novo variants are a leading cause of neurodevelopmental disorders (NDDs), but because every monogenic NDD is different and usually extremely rare, it remains a major challenge to understand the complete phenotype and genotype spectrum of any morbid gene. According to OMIM, heterozygous variants in KDM6B cause "neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities." Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.). Using 3D protein structure analysis and an innovative dual Drosophila gain-of-function assay, we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B. Consistent with the role of KDM6B in human cognition, we demonstrated a role for the Drosophila KDM6B ortholog in memory and behavior. Taken together, we accurately define the broad clinical spectrum of the KDM6B-related NDD, introduce an innovative functional testing paradigm for the assessment of KDM6B variants, and demonstrate a conserved role for KDM6B in cognition and behavior. Our study demonstrates the critical importance of international collaboration, sharing of clinical data, and rigorous functional analysis of genetic variants to ensure correct disease diagnosis for rare disorders.
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Discapacidad Intelectual , Trastornos del Neurodesarrollo , Humanos , Animales , Facies , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Fenotipo , Drosophila , Discapacidad Intelectual/patología , Histona Demetilasas con Dominio de Jumonji/genéticaRESUMEN
Mosaic genome-wide paternal uniparental disomy is an infrequently described disorder in which affected individuals have signs and symptoms that may resemble Beckwith-Wiedemann syndrome. In addition, they can develop multiple benign and malignant tumors throughout life. Routine molecular diagnostics may not detect the (characteristic) low level of mosaicism, and the diagnosis is likely to be missed. Genetic counseling and a life-long alertness for the development of tumors is indicated. We describe the long diagnostic process of a patient who already had a tumor at birth and developed multiple tumors in childhood and adulthood. Furthermore, we offer clues to recognize the entity.
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Cromosomas Humanos/genética , Estudio de Asociación del Genoma Completo , Mosaicismo , Neoplasias/diagnóstico , Neoplasias/genética , Disomía Uniparental/diagnóstico , Disomía Uniparental/genética , Adulto , Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/genética , Femenino , Impresión Genómica , Genotipo , Humanos , Recién Nacido , Masculino , Neoplasias/clasificación , Polimorfismo de Nucleótido Simple , PronósticoRESUMEN
Up to 8.5% of children with cancer have a genetic cause for their cancer: a tumor predisposition syndrome (TPS). Diagnosing a TPS is of great importance, as it may have major consequences for clinical care. Patients with TPSs require specific monitoring and management. We present an overview of the cancer-related and noncancer-related consequences for the 36 most common TPSs.
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Síndromes Neoplásicos Hereditarios/genética , Adolescente , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , MasculinoRESUMEN
INTRODUCTION: Radiotherapy is essential for achieving and maintaining local control in head and neck rhabdomyosarcoma (HNRMS) patients. However, radiotherapy may cause outgrowth disturbances of facial bone and soft tissue, resulting in facial asymmetry. The aim of this study was to develop a method to visualize and measure facial asymmetry in HNRMS survivors using three-dimensional (3D) imaging techniques. METHODS: Facial deformity was evaluated in a multidisciplinary clinical assessment of 75 HNRMS survivors, treated with external beam radiotherapy (EBRT, n = 26) or Ablative surgery, MOulage brachytherapy, and REconstruction (AMORE, n = 49). Individual facial asymmetry was measured using 3D photogrammetry and expressed in a raw asymmetry index and a normalized sex-age-ethnicity-matched asymmetry signature weight. Facial asymmetry was also compared between British and Dutch controls and between survivors and their matched controls. RESULTS: Facial asymmetry was more pronounced with increasing age (P < 0.01) in British controls compared with Dutch controls (P = 0.04). Survivors developed more facial asymmetry than matched controls (P < 0.001). The clinical assessment of facial deformity correlated with the raw asymmetry index (r = 0.60, P < 0.001). DISCUSSION: 3D imaging can be used for objective measurement of facial asymmetry in HNRMS survivors. The raw asymmetry index correlated with a clinical assessment of facial deformity. Comparisons between treatment groups seemed inappropriate given the differences in facial asymmetry between British and Dutch controls. In future studies, pretreatment images could act as matched controls for posttreatment evaluation.
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Asimetría Facial , Neoplasias de Cabeza y Cuello/radioterapia , Imagenología Tridimensional , Rabdomiosarcoma/radioterapia , Sobrevivientes , Adolescente , Adulto , Niño , Preescolar , Asimetría Facial/etiología , Asimetría Facial/patología , Femenino , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Rabdomiosarcoma/patologíaRESUMEN
BACKGROUND: Somatic mosaicism is being increasingly recognised as an important cause of non-Mendelian presentations of hereditary syndromes. A previous whole-exome sequencing study using DNA derived from peripheral blood identified mosaic mutations in DICER1 in two children with overgrowth and developmental delay as well as more typical phenotypes of germline DICER1 mutation. However, very-low-frequency mosaicism is difficult to detect, and thus, causal mutations can go unnoticed. Highly sensitive, cost-effective approaches are needed to molecularly diagnose these persons. We studied four children with multiple primary tumours known to be associated with the DICER1 syndrome, but in whom germline DICER1 mutations were not detected by conventional mutation detection techniques. METHODS AND RESULTS: We observed the same missense mutation within the DICER1 RNase IIIb domain in multiple tumours from different sites in each patient, raising suspicion of somatic mosaicism. We implemented three different targeted-capture technologies, including the novel HaloPlex(HS) (Agilent Technologies), followed by deep sequencing, and confirmed that the identified mutations are mosaic in origin in three patients, detectable in 0.24-31% of sequencing reads in constitutional DNA. The mosaic origin of patient 4's mutation remains to be unequivocally established. We also discovered likely pathogenic second somatic mutations or loss of heterozygosity (LOH) in tumours from all four patients. CONCLUSIONS: Mosaic DICER1 mutations are an important cause of the DICER1 syndrome in patients with severe phenotypes and often appear to be accompanied by second somatic truncating mutations or LOH in the associated tumours. Furthermore, the molecular barcode-containing HaloPlex(HS) provides the sensitivity required for detection of such low-level mosaic mutations and could have general applicability.
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ARN Helicasas DEAD-box/genética , Estudios de Asociación Genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mosaicismo , Mutación , Neoplasias Primarias Múltiples/genética , Ribonucleasa III/genética , Niño , Preescolar , Biología Computacional/métodos , Análisis Mutacional de ADN , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/normas , Humanos , Pérdida de Heterocigocidad , Masculino , Neoplasias Primarias Múltiples/diagnóstico , Fenotipo , Sensibilidad y Especificidad , SíndromeRESUMEN
A group of patients who had cancer as a child were previously found to have distinct patterns of morphological abnormalities. In this study, we investigated the added value of 3D shape analysis to characterize their facial morphology. Primarily, we showed in an objective and quantitative manner that the overall facial dysmorphism of the individuals who had had a childhood cancer was significantly greater than that of the controls. We also demonstrated how the same approach can be used to detect a similar disparity for a more localized malar region comprising customized disconnected patches defined on both sides of the face. In addition, by comparing original face surfaces to their mirrored forms, we confirmed that the patient group had significantly greater facial asymmetry than the controls. Each of these results made use of surface shape differences not detectable by simple linear or angular characteristics as might be used in analyses based on measures captured manually or derived from landmarks annotating 2D photographic images. We conclude that 3D morphometric analysis of a relatively small heterogeneous patient group can further delineate face shape differences from typically developing individuals that are too subtle or geometrically complex to identify or quantify objectively with conventional clinical and anthropometric approaches. © 2016 Wiley Periodicals, Inc.
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Cara/patología , Imagenología Tridimensional , Neoplasias/diagnóstico , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Análisis por Conglomerados , Asimetría Facial , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Procesamiento de Imagen Asistido por Computador , Masculino , Adulto JovenRESUMEN
(Brain) tumors are usually a disorder of aged individuals. If a brain tumor occurs in a child, there is a possible genetic susceptibility for this. Such genetic susceptibilities often show other signs and symptoms. Therefore, every child with a brain tumor should be carefully evaluated for the presence of a "tumor predisposition syndrome." Here, we provide an overview of the various central nervous system tumors that occur in children with syndromes and of the various syndromes that occur in children with brain tumor. Our aim is to facilitate recognition of syndromes in children with a brain tumor and early diagnosis of brain tumors in children with syndromes. Diagnosing tumor predisposition syndromes in children may have important consequences for prognosis, treatment, and screening for subsequent malignancies and nontumor manifestations. We discuss pitfalls in clinical and molecular diagnoses, and the consequences of diagnosing a hereditary disorder for family members. Our improved knowledge of cancer etiology is increasingly translated into management strategies in syndromes in general and will likely lead in the near future to personalized therapeutic approaches for tumor predisposition syndromes.
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Neoplasias Encefálicas/patología , Neoplasias Encefálicas/fisiopatología , Neoplasias Encefálicas/genética , Niño , Preescolar , Predisposición Genética a la Enfermedad , Humanos , SíndromeRESUMEN
BACKGROUND: Distinguishing congenital pulmonary airway malformations (CPAMs) from pleuropulmonary blastoma (PPB) can be challenging. Previously diagnosed patients with CPAM may have been misdiagnosed and we may have missed DICER1-associated PPBs, a diagnosis with important clinical implications for patients and their families. To gain insight in potential misdiagnoses, we systematically assessed somatic DICER1 gene mutation status in an unselected, retrospective cohort of patients with a CPAM diagnosis. METHODS: In the Amsterdam University Medical Center (the Netherlands), it has been standard policy to resect CPAM lesions. We included all consecutive cases of children (age 0-18 years) with a diagnosis of CPAM between 2007 and 2017 at this center. Clinical and radiographic features were reviewed, and DICER1 gene sequencing was performed on DNA retrieved from CPAM tissue samples. RESULTS: Twenty-eight patients with a surgically removed CPAM were included. CPAM type 1 and type 2 were the most common subtypes (n = 12 and n = 13). For 21 patients a chest CT scan was available for reassessment by two pediatric radiologists. In 9 patients (9/21, 43%) the CPAM subtype scored by the radiologists did not correspond with the subtype given at pathology assessment. No pathogenic mutations and no copy number variations of the DICER1 gene were found in the DNA extracted from CPAM tissue (0/28). CONCLUSIONS: Our findings suggest that the initial CPAM diagnoses were correct. These findings should be validated through larger studies to draw conclusions regarding whether systematic DICER1 genetic testing is required in children with a pathological confirmed diagnosis of CPAM or not. LEVEL OF EVIDENCE: Level IV.
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Malformación Adenomatoide Quística Congénita del Pulmón , Blastoma Pulmonar , Niño , Humanos , Recién Nacido , Lactante , Preescolar , Adolescente , Estudios de Cohortes , Estudios Retrospectivos , Blastoma Pulmonar/diagnóstico , Blastoma Pulmonar/genética , Blastoma Pulmonar/cirugía , Malformación Adenomatoide Quística Congénita del Pulmón/diagnóstico por imagen , Malformación Adenomatoide Quística Congénita del Pulmón/genética , Malformación Adenomatoide Quística Congénita del Pulmón/cirugía , ADN , Ribonucleasa III/genética , ARN Helicasas DEAD-box/genéticaRESUMEN
BACKGROUND: Germline data have become widely available in paediatric oncology since the introduction of paired tumour-germline sequencing. To guide best practice in cancer predisposition syndrome (CPS) diagnostics, we aimed to assess the diagnostic yield of extensive germline analysis compared with clinical selection-based genetic testing among all children with cancer. METHODS: In this prospective diagnostic study, all children (aged 0-19 years) with newly diagnosed neoplasms treated in the Netherlands national centre, the Princess Máxima Center for Pediatric Oncology (Utrecht, Netherlands), between June 1, 2020, and July 31, 2022, were offered two approaches to identify CPSs. In a phenotype-driven approach, paediatric oncologists used the McGill Interactive Pediatric OncoGenetic Guidelines tool to select children for referral to a clinical geneticist, and for genetic testing. In a phenotype-agnostic approach, CPS gene panel sequencing (143 genes) was offered to all children. In children declining the research CPS gene panel, 49 CPS genes were still analysed as part of routine diagnostics by the pathologist. Children with a causative CPS identified before neoplasm diagnosis were excluded. The primary objective was to compare the number and type of patients diagnosed with a CPS between the two approaches. FINDINGS: 1052 children were eligible for this study, of whom 733 (70%) completed both the phenotype-driven approach and received phenotype-agnostic CPS gene panel sequencing (143 genes n=600; 49 genes n=133). In 53 children, a CPS was identified: 14 (26%) were diagnosed by the phenotype-driven approach only, 22 (42%) by CPS gene sequencing only, and 17 (32%) by both approaches. In 27 (51%) of the 53 children, the identified CPS was considered causative for the child's neoplasm. Only one (4%) of the 27 causative CPSs was missed by the phenotype-driven approach and was identified solely by phenotype-agnostic CPS gene sequencing. In 26 (49%) children, a CPS with uncertain causality was identified, including 14 adult-onset CPSs. The CPSs with uncertain causality were mainly detected by the phenotype-agnostic approach (21 [81%] of 26). INTERPRETATION: Phenotype-driven genetic testing and phenotype-agnostic CPS gene panel sequencing were complementary. The phenotype-driven approach identified the most causative CPSs. CPS gene panel sequencing identified additional CPSs, many of those with uncertain causality, but some with clinical utility. We advise clinical evaluation for CPSs in all children with neoplasms. Phenotype-agnostic testing of all CPS genes is preferably conducted only in research settings and should be paired with counseling. FUNDING: Stichting Kinderen Kankervrij.
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Background: ELP1 pathogenic variants (PV) have been recently identified as the most frequent variants predisposing to Sonic Hedgehog (SHH) medulloblastomas (MB); however, guidelines are still lacking for genetic counseling in this new syndrome. Methods: We retrospectively reviewed clinical and genetic data of a French series of 29 ELP1-mutated MB. Results: All patients developed SHH-MB, with a biallelic inactivation of PTCH1 found in 24 tumors. Other recurrent alterations encompassed the TP53 pathway and activation of MYCN/MYCL signaling. The median age at diagnosis was 7.3 years (range: 3-14). ELP1-mutated MB behave as sporadic cases, with similar distribution within clinical and molecular risk groups and similar outcomes (5 y - OSâ =â 86%); no unusual side effect of treatments was noticed. Remarkably, a germline ELP1 PV was identified in all patients with available constitutional DNA (nâ =â 26); moreover, all tested familial trio (nâ =â 11) revealed that the PVs were inherited. Two of the 26 index cases from the French series had a family history of MB; pedigrees from these patients and from 1 additional Dutch family suggested a weak penetrance. Apart from MB, no cancer was associated with ELP1 PVs; second tumors reported in 4 patients occurred within the irradiation fields, in the usual time-lapse for expected radiotherapy-induced neoplasms. Conclusions: The low penetrance, the "at risk' age window limited to childhood and the narrow tumor spectrum, question the actual benefit of genetic screening in these patients and their family. Our results suggest restricting ELP1 germline sequencing to patients with SHH-MB, depending on the parents" request.
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Importance: To improve diagnostics of cancer predisposition syndromes (CPSs) in children with cancer, it is essential to evaluate the effect of CPS gene sequencing among all children with cancer and compare it with genetic testing based on clinical selection. However, a reliable comparison is difficult because recent reports on a phenotype-first approach in large, unselected childhood cancer cohorts are lacking. Objective: To describe a national children's cancer center's experience in diagnosing CPSs before introducing routine next-generation sequencing. Design, Setting, and Participants: This retrospective cohort study was conducted at the National Retinoblastoma Treatment Center (Amsterdam, the Netherlands) and the Princess Máxima Center for Pediatric Oncology (Utrecht, Netherlands) and included Dutch pediatric patients with a new diagnosis of neoplasm between June 1, 2018, and December 31, 2019. Follow-up was at least 18 months after neoplasm diagnosis. Data analysis was conducted from July 2021 to February 2022. Exposures: As part of routine diagnostics, pediatric oncologists and ophthalmologists checked for characteristics of CPSs and selected children for referral to clinical geneticists and genetic testing. Main Outcomes and Measures: Detected cancer predisposition syndromes. Results: A total of 824 patients (median [range] age at diagnosis 7.5 [0-18.9] years; 361 girls [44%]) were assessed, including 335 children with a hematological neoplasm (41%) and 489 (59%) with a solid tumor. In 71 of 824 children (8.6%), a CPS was identified, of which most (96%) were identified by a phenotype-driven approach. Down syndrome and neurofibromatosis type 1 were the most common CPSs diagnosed. In 42 of 71 patients (59%), a CPS was identified after these children developed a neoplasm. The specific type of neoplasm was the most frequent indicator for genetic testing, whereas family history played a minor role. Conclusions and Relevance: In this cohort study of children with a neoplasm, the prevalence of CPSs identified by a phenotype-driven approach was 8.6%. The diagnostic approach for identifying CPSs is currently shifting toward a genotype-first approach. Future studies are needed to determine the diagnostic value, as well as possible disadvantages of CPS gene sequencing among all children with cancer compared with the phenotype-driven approach.
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Neurofibromatosis 1 , Humanos , Estudios de Cohortes , Estudios Retrospectivos , Susceptibilidad a Enfermedades , GenotipoAsunto(s)
Neoplasias Renales , Tumor de Wilms , Fosfatidilinositol 3-Quinasa Clase I , Humanos , MutaciónRESUMEN
PTEN: hamartoma tumor syndrome (PHTS) is a group of syndromes caused by mutations in PTEN. Gorham-Stout phenomenon (GSP) is a rare condition characterized by proliferation of vascular structures in bones, resulting in progressive osteolysis. Here we present a 1-year-old boy with PHTS and GSP. The lesion that later proved to be GSP was evident from the age of 4 months, and became symptomatic at the age of 1 year. Eventually, he developed a fatal chylothorax. Mutation analysis revealed a germline heterozygous mutation c.517 C>T (p.Arg173Cys) in exon 6 of PTEN. Analysis of the lymphatic malformation (LM) tissue revealed no loss of heterozygosity (LOH) nor a second, somatic PTEN mutation of the remaining wild type allele. The germline p.Arg173Cys mutation was also present in the mother and the propositus' younger sister and brother. Further molecular work-up showed a heterozygous variant c.2180C>T (p.Ala727Val) FLT4 in the LM tissue, which was also present in the germline of mother and two siblings. GSP has not been reported before in a patient with a PTEN mutation. Up to this date, this mutation is the only genetic defect possibly involved in the etiology of GSP which is plausible given the known function of PTEN in angiogenic signaling.
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Síndrome de Hamartoma Múltiple/diagnóstico , Osteólisis Esencial/diagnóstico , Familia , Resultado Fatal , Mutación de Línea Germinal , Síndrome de Hamartoma Múltiple/genética , Heterocigoto , Humanos , Lactante , Masculino , Osteólisis Esencial/genética , Fosfohidrolasa PTEN/genéticaRESUMEN
Background and Objective; Genetic risk factors for childhood cancer may also influence facial morphology. 3D photography can be used in the recognition of differences in face shape among individuals. In previous research, 3D facial photography was used to identify increased facial asymmetry and greater deviation from normal facial morphology in a group of individuals with distinct morphological features who had childhood cancer compared to healthy controls. In this study, we aim to determine whether there is a difference in facial morphology between children with cancer without previously selected morphological features and healthy controls, detected with 3D facial photography. METHODS: Facial 3D photographic images were obtained of children with a newly diagnosed malignancy. The resulting sample comprised 13 different cancer types. Patients were excluded if they had a known genetic cause of the cancer. Patients were compared to healthy controls, matched for sex, age and ethnic background. The degree of asymmetry and overall deviation of an individual's face from an age and sex typical control face were measured. RESULTS: A total of 163 patients of European descent were included. No significant difference in asymmetry between patients and controls could be identified. On average, patients deviated more from an age and sex typical face than the controls. CONCLUSION: This study shows that children with cancer deviate more than controls, possibly suggesting a higher prevalence of genetic anomalies within this group. The results suggest that this is not sufficient to discriminate patients from controls. Further research is necessary to explore the patterns of individual variation among the overall deviation of patients and controls.
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Imagenología Tridimensional , Neoplasias , Niño , Cara , Asimetría Facial/diagnóstico por imagen , Humanos , FotograbarRESUMEN
Recognizing a tumor predisposition syndrome (TPS) in a child with cancer is of clinical relevance. Earlier we developed a screening tool to increase diagnostic accuracy and clinical efficiency of identifying TPSs in children with cancer. Here we report on the value of this tool in clinical practice. TuPS is a prospective, observational, multi-center study including children newly diagnosed with cancer from 2016 to 2019 in the Netherlands. Children in whom a TPS had been diagnosed before the cancer diagnosis were excluded. The screening tool consists of a checklist, 2D and 3D photographic series and digital assessment of these by a clinical geneticist. If a TPS was suspected, the patient was assessed positive and referred for routine genetic consultation. Primary aim was to assess the clinical value of this new screening tool. Of the 363 included patients, 57% (208/363) were assessed positive. In 15% of patients (32/208), the 2D photographic series with (n = 12) or without (n = 20) 3D photographs were decisive in the positive assessment. In 2% (4/208) of positive assessed patients, a TPS was diagnosed, and in an additional 2% (4/208) a germline variant of uncertain significance was found. Thirty-five negatively assessed patients were evaluated through routine genetic consultation as controls, in none a TPS was detected. Using the screening tool, 57% of the patients were assessed as suspected for having a TPS. No false negative results were identified in the negative control group in the clinical care setting. The observed prevalence of TPS was lower than expected, due to selection bias in the cohort.
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Neoplasias , Niño , Detección Precoz del Cáncer , Humanos , Tamizaje Masivo , Neoplasias/diagnóstico , Neoplasias/genética , Estudios Prospectivos , SíndromeRESUMEN
INTRODUCTION: Recognising a tumour predisposition syndrome (TPS) in childhood cancer patients is of major clinical relevance. The presence of a TPS may be suggested by the type of tumour in the child. We present an overview of 23 childhood tumours that in themselves should be a reason to refer a child for genetic consultation. METHODS: We performed a PubMed search to review the incidence of TPSs in children for 85 tumour types listed in the International Classification of Childhood Cancer third edition (ICCC-3). The results were discussed during a national consensus meeting with representative clinical geneticists from all six academic paediatric oncology centres in The Netherlands. A TPS incidence of 5% or more was considered a high probability and therefore in itself a reason for referral to a clinical geneticist. RESULTS: The literature search resulted in data on the incidence of a TPS in 26 tumours. For 23/26 tumour types, a TPS incidence of 5% or higher was reported. In addition, during the consensus meeting the experts agreed that children with any carcinoma should always be referred for clinical genetic consultation as well, as it may point to a TPS. CONCLUSION: We present an overview of 23 paediatric tumours with a high probability of a TPS; this will facilitate paediatric oncologists to decide which patients should be referred for genetic consultation merely based on type of tumour.
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Asesoramiento Genético , Predisposición Genética a la Enfermedad , Síndromes Neoplásicos Hereditarios/epidemiología , Niño , Humanos , Incidencia , Derivación y ConsultaRESUMEN
INTRODUCTION: Recognising a tumour predisposition syndrome (TPS) in patients with childhood cancer is of significant clinical relevance, as it affects treatment, prognosis and facilitates genetic counselling. Previous studies revealed that only half of the known TPSs are recognised during standard paediatric cancer care. In current medical practice it is impossible to refer every patient with childhood cancer to a clinical geneticist, due to limited capacity for routine genetic consultation. Therefore, we have developed a screening instrument to identify patients with childhood cancer with a high probability of having a TPS. The aim of this study is to validate the clinical screening instrument for TPS in patients with childhood cancer. METHODS AND ANALYSIS: This study is a prospective nationwide cohort study including all newly diagnosed patients with childhood cancer in the Netherlands. The screening instrument consists of a checklist, two- and three-dimensional photographic series of the patient. 2 independent clinical geneticists will assess the content of the screening instrument. If a TPS is suspected based on the instrument data and thus further evaluation is indicated, the patient will be invited for full genetic consultation. A negative control group consists of 20% of the patients in whom a TPS is not suspected based on the instrument; they will be randomly invited for full genetic consultation. Primary outcome measurement will be sensitivity of the instrument. ETHICS AND DISSEMINATION: The Medical Ethical Committee of the Academic Medical Centre stated that the Medical Research Involving Human Subjects Act does not apply to this study and that official approval of this study by the Committee was not required. The results will be offered for publication in peer-reviewed journals and presented at International Conferences on Oncology and Clinical Genetics. The clinical data gathered in this study will be available for all participating centres. TRIAL REGISTRATION NUMBER: NTR5605.
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Enfermedades Genéticas Congénitas/diagnóstico , Tamizaje Masivo/métodos , Neoplasias/genética , Adolescente , Lista de Verificación , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Recién Nacido , Masculino , Neoplasias/etiología , Países Bajos , Fotograbar , Estudios Prospectivos , Proyectos de Investigación , SíndromeRESUMEN
3D analysis of facial morphology has delineated facial phenotypes in many medical conditions and detected fine grained differences between typical and atypical patients to inform genotype-phenotype studies. Next-generation sequencing techniques have enabled extremely detailed genotype-phenotype correlative analysis. Such comparisons typically employ control groups matched for age, sex and ethnicity and the distinction between ethnic categories in genotype-phenotype studies has been widely debated. The phylogenetic tree based on genetic polymorphism studies divides the world population into nine subpopulations. Here we show statistically significant face shape differences between two European Caucasian populations of close phylogenetic and geographic proximity from the UK and The Netherlands. The average face shape differences between the Dutch and UK cohorts were visualised in dynamic morphs and signature heat maps, and quantified for their statistical significance using both conventional anthropometry and state of the art dense surface modelling techniques. Our results demonstrate significant differences between Dutch and UK face shape. Other studies have shown that genetic variants influence normal facial variation. Thus, face shape difference between populations could reflect underlying genetic difference. This should be taken into account in genotype-phenotype studies and we recommend that in those studies reference groups be established in the same population as the individuals who form the subject of the study.
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Cara/anatomía & histología , Estudios de Asociación Genética , Filogenia , Población Blanca/genética , Adulto , Femenino , Humanos , Masculino , Países Bajos , Fenotipo , Reino UnidoRESUMEN
BACKGROUND: Identification of tumour predisposition syndromes in patients who have cancer in childhood is paramount for optimal care. A screening instrument that can help to identify such patients will facilitate physicians caring for children with cancer. The complete screening instrument should consist of a standardised series of pictures and a screening form for manifestations not visible in the pictures. Here we describe the development of such a screening form based on an international two-stage Delphi process and an initial validation of the complete instrument. PATIENTS AND METHODS: We identified manifestations that may contribute to the diagnosis of a tumour predisposition syndrome through the Winter-Baraitser Dysmorphology Database and the textbook "Gorlin's Syndromes of the Head and Neck". In a two-round Delphi process, eight international content-experts scored the contribution of each of these manifestations. We performed a clinical validation of the instrument in a selected cohort of 10 paediatric cancer patients from another centre. RESULTS: In total, 49 manifestations were found to contribute to the diagnosis of a tumour predisposition syndrome and were included in the screening form. The pilot validation study showed that patients suspected of having a tumour predisposition syndrome were recognised. Excellent correlation for indications of patient's referral between the screening instrument and the reference standard (personal evaluation by an experienced clinical geneticist) was found. CONCLUSIONS: The Delphi process performed by international specialists with a function as opinion leaders in their field of expertise, has led to a screening instrument for childhood cancer patients. Patients who may have a tumour predisposition syndrome and thus have an indication to be referred for further genetic analysis, can be identified using the screening instrument.
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Detección Precoz del Cáncer/métodos , Neoplasias/diagnóstico , Lesiones Precancerosas/diagnóstico , Niño , Estudios de Cohortes , Técnica Delphi , Detección Precoz del Cáncer/instrumentación , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Masculino , Neoplasias/genética , Neoplasias/patología , Proyectos Piloto , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: It is well known that the thyroid gland is sensitive to the damaging effects of irradiation (X-radiation or (131)I¯). For this reason, during exposure to (131)I- metaiodobenzylguanidine (MIBG) in children with neuroblastoma (NBL), the thyroid gland is protected against radiation damage by the administration of either potassium iodide (KI) or a combination of KI, thyroxine, and methimazole. Although hypothyroidism and benign thyroid nodules are frequently encountered during follow-up of these children, differentiated thyroid carcinoma (DTC) has never been reported after treatment with (131)I-MIBG in children who have not been given external beam irradiation. Here, we describe the first two cases of DTC after (131)I-MIBG-therapy. PATIENT FINDINGS: A 6-year-old boy, treated with (131)I-MIBG for NBL at the age of 4 months, and a 13-year-old girl, treated at the age of 9 months, were both diagnosed with DTC at 5 and 12 years after (131)I-MIBG treatment, respectively. Both children received thyroid protection during exposure to (131)I-MIBG. In each child DTC was discovered in nonpalpable nodules by thyroid ultrasound. SUMMARY: The first two pediatric patients with DTC after treatment with (131)I-MIBG are reported. CONCLUSIONS: Both these cases of DTC after (131)I-MIBG for childhood NBL underline the importance of adequate thyroid protection against radiation exposure during treatment for NBL. Children who have been treated with (131)I-MIBG should be given life-long follow-up, not only with regard to thyroid function, but also with surveillance for the development of thyroid nodules and thyroid cancer.