NF1 with 47,XYY mosaicism diagnosed by mandibular neurofibromas
HGV database
The relevant data from this Data Report are hosted at the Human Genome Variation Database at https://doi.org/10.6084/m9.figshare.hgv.3400.
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Cancer-independent somatic mutation of the wild-type NF1 allele in normal tissues in neurofibromatosis type 1
Cancer predisposition syndromes mediated by recessive cancer genes generate tumors via somatic variants (second hits) in the unaffected allele. Second hits may or may not be sufficient for neoplastic transformation. Here we performed whole-genome and whole-exome sequencing on 479 tissue biopsies from a child with neurofibromatosis type 1, a multisystem cancer-predisposing syndrome mediated by constitutive monoallelic NF1 inactivation. We identified multiple independent NF1 driver variants in histologically normal tissues, but not in 610 biopsies from two nonpredisposed children. We corroborated this finding using targeted duplex sequencing, including a further nine adults with the same syndrome. Overall, truncating NF1 mutations were under positive selection in normal tissues from individuals with neurofibromatosis type 1. We demonstrate that normal tissues in neurofibromatosis type 1 commonly harbor second hits in NF1, the extent and pattern of which may underpin the syndrome’s cancer phenotype.
Genotypes and phenotypes of neurofibromatosis type 1 patients in Japan: A Hereditary Tumor Cohort Study
Neurofibromatosis type 1 (NF1) presents with a broad spectrum of clinical manifestations, including an increased risk of tumor development and hypertension. Comprehensive data on genotype‒phenotype correlations in patients with NF1 are limited. Therefore, in this study, we aimed to elucidate the detailed genetic and clinical characteristics of NF1 in a hereditary tumor cohort. We performed sequencing and copy number assays in a clinical laboratory and analyzed the clinical data of 44 patients with suspected NF1. Germline pathogenic variants were detected in 36 patients (81.8%), and 20.7% of the variants were novel. Notably, 40.0% of adult patients presented with malignancies; female breast cancer occurred in 20.0% of patients, which was a higher rate than that previously reported. Hypertension was observed in 30.6% of the adult patients, with one patient experiencing sudden death and another developing pheochromocytoma. Three patients with large deletions in NF1 exhibited prominent cutaneous, skeletal, and neurological manifestations. These results highlight the importance of regular surveillance, particularly for patients with malignancies and hypertension. Our findings provide valuable insights for genetic counseling and clinical management, highlighting the multiple health risks associated with NF1 and the need for comprehensive and multidisciplinary care.
FGFR antagonists restore defective mandibular bone repair in a mouse model of osteochondrodysplasia
Gain-of-function mutations in fibroblast growth factor receptor (FGFR) genes lead to chondrodysplasia and craniosynostoses. FGFR signaling has a key role in the formation and repair of the craniofacial skeleton. Here, we analyzed the impact of Fgfr2– and Fgfr3-activating mutations on mandibular bone formation and endochondral bone repair after non-stabilized mandibular fractures in mouse models of Crouzon syndrome (Crz) and hypochondroplasia (Hch). Bone mineralization of the calluses was abnormally high in Crz mice and abnormally low in Hch mice. The latter model presented pseudarthrosis and impaired chondrocyte differentiation. Spatial transcriptomic analyses of the Hch callus revealed abnormally low expression of Col11, Col1a, Dmp1 genes in mature chondrocytes. We found that the expression of genes involved in autophagy and apoptosis (Smad1, Comp, Birc2) was significantly perturbed and that the Dusp3, Dusp9, and Socs3 genes controlling the mitogen-activated protein kinase pathway were overexpressed. Lastly, we found that treatment with a tyrosine kinase inhibitor (BGJ398, infigratinib) or a C-type natriuretic peptide (BMN111, vosoritide) fully rescued the defective endochondral bone repair observed in Hch mice. Taken as a whole, our findings show that FGFR3 is a critical orchestrator of bone repair and provide a rationale for the development of potential treatments for patients with FGFR3-osteochondrodysplasia.
Expert consensus on orthodontic treatment of protrusive facial deformities
Protrusive facial deformities, characterized by the forward displacement of the teeth and/or jaws beyond the normal range, affect a considerable portion of the population. The manifestations and morphological mechanisms of protrusive facial deformities are complex and diverse, requiring orthodontists to possess a high level of theoretical knowledge and practical experience in the relevant orthodontic field. To further optimize the correction of protrusive facial deformities, this consensus proposes that the morphological mechanisms and diagnosis of protrusive facial deformities should be analyzed and judged from multiple dimensions and factors to accurately formulate treatment plans. It emphasizes the use of orthodontic strategies, including jaw growth modification, tooth extraction or non-extraction for anterior teeth retraction, and maxillofacial vertical control. These strategies aim to reduce anterior teeth and lip protrusion, increase chin prominence, harmonize nasolabial and chin-lip relationships, and improve the facial profile of patients with protrusive facial deformities. For severe skeletal protrusive facial deformities, orthodontic-orthognathic combined treatment may be suggested. This consensus summarizes the theoretical knowledge and clinical experience of numerous renowned oral experts nationwide, offering reference strategies for the correction of protrusive facial deformities.
Germline mosaicism in TCF20-associated neurodevelopmental disorders: a case study and literature review
Autosomal dominant variants in transcription factor 20 (TCF20) can result in TCF20-associated neurodevelopmental disorder (TAND), a condition characterized by developmental delay and intellectual disability, autism, dysmorphisms, dystonia, and variable other neurological features. To date, a total of 91 individuals with TAND have been reported; ~67% of cases arose de novo, while ~10% were inherited, and, intriguingly, ~8% were either confirmed or suspected to have arisen via germline mosaicism. Here, we describe two siblings with a developmental condition characterized by intellectual disability, autism, a circadian rhythm sleep disorder, and attention deficit hyperactivity disorder (ADHD) caused by a novel heterozygous single nucleotide deletion in the TCF20 gene, NM_001378418.1:c.4737del; NP_001365347.1:p.Lys1579Asnfs*36 (GRCh38/hg38). The variant was not detected in DNA extracted from peripheral blood in either parent by Sanger sequencing of PCR-generated amplicons, or by deep sequencing of PCR amplicons using MiSeq and MinION. However, droplet digital PCR (ddPCR) of DNA derived from early morning urine detected the variation in 3.2% of the father’s urothelial cells, confirming germline mosaicism. This report is only the second to confirm with physical evidence TCF20 germline mosaicism and discusses germline mosaicism as a likely under-detected mode of inheritance in neurodevelopmental conditions.
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