-related disorder in 87 adults: Natural history and self-sustainability.

Purpose: is one of the most frequently mutated genes in intellectual disability cohorts. Thus, far few adult-aged patients with -related disorder have been described, which limits our understanding of the disease's natural history and our ability to counsel patients and their families.

Methods: Data on patients aged 18+ years with -related disorder were collected through an online questionnaire completed by clinicians and parents.

CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature.

Neurodevelopmental disorder with or without autism or seizures (NEDAUS) is a neurodevelopmental disorder characterized by global developmental delay, speech delay, seizures, autistic features, and/or behavior abnormalities. It is caused by CUL3 (Cullin-3 ubiquitin ligase) haploinsufficiency. We collected clinical and molecular data from 26 individuals carrying pathogenic variants and variants of uncertain significance (VUS) in the CUL3 gene, including 20 previously unreported cases.

Comparison of clinical selection-based genetic testing with phenotype-agnostic extensive germline sequencing to diagnose genetic predisposition in children with cancer: a prospective diagnostic study.

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.

Medulloblastomas with pathogenic variants: A weakly penetrant syndrome with a restricted spectrum in a limited age window.

Background: 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 -mutated MB.

Results: All patients developed SHH-MB, with a biallelic inactivation of found in 24 tumors.

No Pathogenic DICER1 Gene Variants in a Cohort Study of 28 Children With Congenital Pulmonary Airway Malformation.

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.

Assessment of Cancer Predisposition Syndromes in a National Cohort of Children With a Neoplasm.

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.

Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature.

Purpose: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD.

Prevalence of (Epi)genetic Predisposing Factors in a 5-Year Unselected National Wilms Tumor Cohort: A Comprehensive Clinical and Genomic Characterization.

Purpose: Wilms tumor (WT) is associated with (epi)genetic predisposing factors affecting a growing number of WT predisposing genes and loci, including those causing Beckwith-Wiedemann spectrum (BWSp) or -related syndromes. To guide genetic counseling and testing, we need insight into the prevalence of WT predisposing (epi)genetic factors.

Patients And Methods: All children diagnosed with WT in the Netherlands between 2015 and 2020 were referred to a clinical geneticist.

3D analysis of facial morphology in Dutch children with cancer.

Unlabelled: 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.

Uncemented total hip arthroplasty; increased risk of early periprosthetic fracture requiring revision surgery in elderly females.

Purpose: The preferred method of stem fixation in total hip arthroplasty (THA) remains debatable. Uncemented THA favors a lower rate of aseptic loosening but has an increased risk of early periprosthetic fractures (EPF). We hypothesize that routine placement of uncemented THA by experienced surgeons diminishes this EPF-risk.

Current recommendations for cancer surveillance in Gorlin syndrome: a report from the SIOPE host genome working group (SIOPE HGWG).

Gorlin syndrome (MIM 109,400), a cancer predisposition syndrome related to a constitutional pathogenic variation (PV) of a gene in the Sonic Hedgehog pathway (PTCH1 or SUFU), is associated with a broad spectrum of benign and malignant tumors. Basal cell carcinomas (BCC), odontogenic keratocysts and medulloblastomas are the main tumor types encountered, but meningiomas, ovarian or cardiac fibromas and sarcomas have also been described. The clinical features and tumor risks are different depending on the causative gene.

Clinical value of a screening tool for tumor predisposition syndromes in childhood cancer patients (TuPS): a prospective, observational, multi-center study.

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.

Multiple tumors due to mosaic genome-wide paternal uniparental disomy.

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.

Development and feasibility of a guided and tailored internet-based cognitive-behavioural intervention for kidney donors and kidney donor candidates.

Objectives: Living donor kidney transplantation is currently the preferred treatment for patients with end-stage renal disease. A subgroup of the kidney donor population experiences adjustment problems during or after the donation procedure (eg, anxiety or fatigue). There is a need for evidence-based interventions that decrease donation-related difficulties before or after donation.

High Yield of Pathogenic Germline Mutations Causative or Likely Causative of the Cancer Phenotype in Selected Children with Cancer.

In many children with cancer and characteristics suggestive of a genetic predisposition syndrome, the genetic cause is still unknown. We studied the yield of pathogenic mutations by applying whole-exome sequencing on a selected cohort of children with cancer. To identify mutations in known and novel cancer-predisposing genes, we performed trio-based whole-exome sequencing on germline DNA of 40 selected children and their parents.

Consequences of diagnosing a tumor predisposition syndrome in children with cancer: A literature review.

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.

Phenotypes and genotypes in individuals with SMC1A variants.

SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS.

Childhood tumours with a high probability of being part of a tumour predisposition syndrome; reason for referral for genetic consultation.

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.

Facial asymmetry in head and neck rhabdomyosarcoma survivors.

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.

Validation of a clinical screening instrument for tumour predisposition syndromes in patients with childhood cancer (TuPS): protocol for a prospective, observational, multicentre study.

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.

A neonate with a unique non-Down syndrome transient proliferative megakaryoblastic disease.

Transient myeloproliferative disorder (TMD) is a leukemia type that occurs typically in newborns. In Down syndrome, TMD is referred to as transient abnormal myelopoiesis (TAM). Recently, transientness has also been reported in acute myeloid leukemia patients with germline trisomy 21 mosaicism, and even in cases with somatic trisomy 21, with or without GATA1 mutations.

3D morphometry aids facial analysis of individuals with a childhood cancer.

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.

Phenotype, cancer risk, and surveillance in Beckwith-Wiedemann syndrome depending on molecular genetic subgroups.

Patients with Beckwith-Wiedemann syndrome (BWS) have an increased risk to develop cancer in childhood, especially Wilms tumor and hepatoblastoma. The risk varies depending on the cause of BWS. We obtained clinical and molecular data in our cohort of children with BWS, including tumor occurrences, and correlated phenotype and genotype.