Primary lymphatic anomalies may present in a myriad of ways and are highly heterogenous. Careful consideration of the presentation can lead to an accurate clinical and/or molecular diagnosis which ...will assist with management. The most common presentation is lymphoedema, swelling resulting from failure of the peripheral lymphatic system. However, there may be internal lymphatic dysfunction, for example, chylous reflux, or lymphatic malformations, including the thorax or abdomen. A number of causal germline or postzygotic gene mutations have been discovered. Some through careful phenotyping and categorisation of the patients based on the St George’s classification pathway/algorithm. The St George’s classification algorithm is aimed at providing an accurate diagnosis for patients with lymphoedema based on age of onset, areas affected by swelling and associated clinical features. This has enabled the identification of new causative genes. This update brings the classification of primary lymphatic disorders in line with the International Society for the Study of Vascular Anomalies 2018 classification for vascular anomalies. The St George’s algorithm considers combined vascular malformations and primary lymphatic anomalies. It divides the types of primary lymphatic anomalies into lymphatic malformations and primary lymphoedema. It further divides the primary lymphoedema into syndromic, generalised lymphatic dysplasia with internal/systemic involvement, congenital-onset lymphoedema and late-onset lymphoedema. An audit and update of the algorithm has revealed where new genes have been discovered and that a molecular diagnosis was possible in 26% of all patients overall and 41% of those tested.
Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are ...severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM).
To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency.
We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM.
Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies.
This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L'Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US).
The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human ...phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online.
Background
Mammography alone is an ineffective method for breast cancer surveillance and diagnosing cancer recurrence. The aim was to evaluate the ability of artificial intelligence (AI) to read ...digital mammograms as an additive tool to exclude recurrence in the operative bed of known breast cancer patients following the different surgical procedures.
Methods
We used a retrospective cohort study of post-surgery mammograms (n = 577). Imaging was performed within 6 months after the surgery or more. The AI solution used to read mammograms (AI-MMG) provided a targeted heat map of the operative bed, which was supported by a decision likelihood score percentage of cancer recurrence. The reference for suspicious or malignant-looking abnormalities (n = 62, 12.3%) was diagnosed by biopsy. A clear operative bed and benign-looking changes (n = 442) were confirmed by ultrasound characterization patterns and one year of intermittent follow-up.
Results
The AI scoring percentage for a clear operative bed ranged between 0 and 26%, with a mean of 15% ± 5.4%. Operative bed benign changes ranged from 10 to 88%, with a mean of 48.2% ± 21.2%, while malignancy recurrence ranged from 65 to 99%, with an average of 87.7% ± 10.5%. The “ROC: Receiver Operating Characteristic” curve for AI to predict cancer in the surgical bed on mammograms was 0.906. The optimum cutoff value to distinguish between benign postoperative alterations and malignancy recurrence was 56.5% (95%, CI 0.824–1.060,
p
value < 0.001).
Excellent agreement between AI-MMG and pathology or ultrasound results was observed, and Kappa was 0.894,
p
value < 0.001.
Conclusions
The use of artificial intelligence has enhanced the diagnostic performance of the postoperative mammograms to rule out recurrent malignancies in breast cancer surveillance.
Introduction:
SHORT syndrome is a rare autosomal dominant condition described by its acronym of short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger ...abnormality, and teething delay. Individuals have a distinct progeroid craniofacial appearance with a triangular face, frontal bossing, hypoplastic or thin alae nasi, large low-set ears, and mandibular retrognathia.
Objectives:
To systematically appraise the literature and update the clinical phenotype with emphasis on the dental condition.
Design:
A systematic literature search was carried out to update the clinical phenotype, identifying reports of individuals with SHORT syndrome published after August 2015. The same search strategy but not limited to publication date was carried out to identify reports of the dental phenotype. Two independent reviewers screened 1937 articles with 55 articles identified for full-text review.
Results:
Nineteen individuals from 11 families were identified. Facial dysmorphism including ocular depression, triangular shaped face, frontal bossing, large low-set ears, and micrognathia were the most consistent features followed by lipodystrophy, insulin resistance, and intrauterine growth restriction. Teething delay, microdontia, hypodontia, and enamel hypoplasia have all been reported.
Conclusion:
Features that comprise the SHORT acronym do not accurately or completely describe the clinical phenotype. The craniofacial appearance is one of the most consistent features. Lipodystrophy and insulin resistance may also be considered cardinal features. After teething delay, enamel hypoplasia and microdontia are the most common dental manifestations. We present recommendations for the dental and orthodontic/orthognathic management of individuals with SHORT syndrome.
The regulated proliferation and differentiation of neural stem cells before the generation and migration of neurons in the cerebral cortex are central aspects of mammalian development. ...Periventricular neuronal heterotopia, a specific form of mislocalization of cortical neurons, can arise from neuronal progenitors that fail to negotiate aspects of these developmental processes. Here we show that mutations in genes encoding the receptor-ligand cadherin pair DCHS1 and FAT4 lead to a recessive syndrome in humans that includes periventricular neuronal heterotopia. Reducing the expression of Dchs1 or Fat4 within mouse embryonic neuroepithelium increased progenitor cell numbers and reduced their differentiation into neurons, resulting in the heterotopic accumulation of cells below the neuronal layers in the neocortex, reminiscent of the human phenotype. These effects were countered by concurrent knockdown of Yap, a transcriptional effector of the Hippo signaling pathway. These findings implicate Dchs1 and Fat4 upstream of Yap as key regulators of mammalian neurogenesis.
Background
The enhancement overlaps at contrast-enhanced mammogram (CEM) between benign and malignant breast abnormalities presents a high probability of false-positive lesions and subjects females’ ...candidate for screening and diagnostic mammograms to unnecessary biopsy and anxiety. The current work aimed to evaluate the ability of mammograms scanned by artificial intelligence (AI) to enhance the specificity of CEM and support the probability of malignancy in suspicious and malignant looking breast lesions.
Methods
The study included 1524 breast lesions. The AI algorithm applied to the initial mammograms and generated location information for lesions. AI scoring suggested the probability of malignancy ranged from 100% (definite cancers) and < 10% (definite non-cancer) and correlated with recombinant contrast enhanced images.
Results
The malignant proved abnormalities were 1165 (76.5%), and the benign ones were 359 (26.5%). BI-RADS 4 category was assigned in 704 lesions (46.2%) divided into 400 malignant (400/704, 56.8%) and 304 benign (304/704, 43.2%). BI-RADS 5 category presented by 820 lesions (53.8%), 765 of them were malignant (765/820, 93.3%) and 55 were benign (55/820, 6.7%). The sensitivity of digital mammogram whether supported by AI (93.9%) or contrast media (94.4%) was significantly increased to 97.2% (
p
< 0.001) when supported by both methods. Improvement of the negative predictive value (from 80.6% and 79.6% to 89.8%,
p
< 0.05) and the accuracy (from 91.1 and 88.8 to 94.0%,
p
< 0.01) was detected.
Conclusions
Contrast-enhanced mammogram helps in specification of different breast lesions in view of patterns of contrast uptake and morphology descriptors, yet with some overlap. The use of artificial intelligence applied on digital mammogram reduced the interpretational variability and limited attempts of re-biopsies of suspicious looking breast lesions assessed by contrast-enhanced mammograms.
Individuals with the three base pair deletion NM_000267.3(NF1):c.2970_2972del p.(Met992del) have been recognised to present with a milder neurofibromatosis type 1 (NF1) phenotype characterised by ...café-au-lait macules (CALs) and intertriginous freckling, as well as a lack of cutaneous, subcutaneous and plexiform neurofibromas and other NF1-associated complications. Examining large cohorts of patients over time with this specific genotype is important to confirm the presentation and associated risks of this variant across the lifespan. Forty-one individuals with the in-frame NF1 deletion p.Met992del were identified from 31 families. Clinicians completed a standardised clinical questionnaire for each patient and the resulting data were collated and compared to published cohorts. Thirteen patients have been previously reported, and updated clinical information has been obtained for these individuals. Both CALs and intertriginous freckling were present in the majority of individuals (26/41, 63%) and the only confirmed features in 11 (27%). 34/41 (83%) of the cohort met NIH diagnostic criteria. There was a notable absence of all NF1-associated tumour types (neurofibroma and glioma). Neurofibroma were observed in only one individual-a subcutaneous lesion (confirmed histologically). Nineteen individuals were described as having a learning disability (46%). This study confirms that individuals with p.Met992del display a mild tumoural phenotype compared to those with 'classical', clinically diagnosed NF1, and this appears to be the case longitudinally through time as well as at presentation. Learning difficulties, however, appear to affect a significant proportion of NF1 subjects with this phenotype. Knowledge of this genotype-phenotype association is fundamental to accurate prognostication for families and caregivers.
Highlights • We studied interpretation criteria for enhancing lesions on CESM. • We evaluated the enhancement patterns of 211 breast lesions. • Our results proved that CESM minimized positive and ...negative falsies in DM. • The proposed CESM lexicon helped in characterization and categorization.
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