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Mosaic disorders affecting pigmentation - part 1: how to make a clinical diagnosis.
No full textMosaic disorders affecting pigmentation are a large group of different rare diseases which present with hypo- and/or hyper-pigmented birthmarks. These can carry associated risks such as involvement of other organ systems, a predisposition to cancer, and the possibility of transmission to future offspring as germline disease. However, clinical diagnosis of these conditions has been notoriously difficult, due not only to the rarity of the conditions, but to the similarity of their cutaneous signs and the massive intra-disease variability intrinsic to their pathogenetic mechanism. This review draws on the genetic and clinical discoveries of the last decade to introduce key concepts such as how to define a mosaic disorder, the relevance of small single pigmentary birthmarks, the occurrence of "post-natal birthmarks", and the defining clinical features of mosaic disorders affecting pigmentation. It then lays out a modular classification for use in clinical practice and research studies, based on two independently variable clinical features of the cutaneous signs - the developmental pattern, and the lesion type. The classification for the first time brings together macular lesions as well as naevi, epidermal as well as dermal lesions, and hyper- as well as hypo-pigmented, reflecting this unifying overview of the aetiology of birthmarks affecting pigmentation. A companion smartphone iOS app for the clinical classification has been designed for use in clinic and is freely available online at What'sThatSpot. The clinical importance of distinguishing mosaic disorders from germline disorders presenting with the same developmental patterns is discussed in the context of differential diagnoses. The third modular component of the classification - genotype - is addressed in the second part of this review
Segmental macular hyperpigmentation: new genes, new clinical implications.
No full textBACKGROUND: Segmental macular hyperpigmentation (SMH) is macular hyperpigmentation in a defined developmental pattern, presenting at birth or in the early years. The only known cause of this phenotype has been mosaicism in gene GNAS, as part of McCune-Albright syndrome. It is unknown how often GNAS mosaicism is the cause of SMH presenting to Dermatology, or whether there are other genetic causes for the phenotype with different clinical implications. OBJECTIVES: To investigate the genetic causes of SMH, and the natural history of the condition. METHODS: A large prospective cohort of 50 children were recruited consecutively for phenotypic and genotypic studies over a period of 15 years. High-depth next-generation sequencing of affected skin with bioinformatic analysis optimised for mosaic variant detection was performed in 42. RESULTS: Three patients with mosaic GNAS variants were identified, all otherwise well at presentation, but one of whom went on to develop endocrine complications during the follow-up period. Importantly, in a further five patients, new genetic causes were identified. These were pathogenic mosaic variants in single genes (NRAS (n=2), BRAF (n=1), PTPN11 (n=1) and a mosaic chromosomal copy number variant (chromosome 5p gain (n=1)), all undetectable in blood. In most cases, the variant allele frequency was extremely low, likely reflecting the very few variant cells in a whole skin biopsy of a macular lesion, and it is possible that causative variants in other patients are still being missed even at current testing sensitivities. CONCLUSIONS: The discovery of these highly disparate genetic causes has important implications for individualised patient management. Specifically detection of GNAS variants will involve monitoring and investigation of other systems, NRAS/BRAF/PTPN11 will involve discussion of melanoma awareness and the potential of passing on variants as germline diseases to future offspring, and chromosomal abnormalities may have implications in multiple areas. Our findings multiply the known causes of SMH and reveal the importance of genotyping patients presenting to Dermatology, even when clinically well
Oxidative stress, inflammation and altered glucose metabolism contribute to the retinal phenotype in the choroideremia zebrafish
No full textReactive oxygen species (ROS) within the retina play a key role in maintaining function and cell survival. However, excessive ROS can lead to oxidative stress, inducing dysregulation of metabolic and inflammatory pathways. The chmru848 zebrafish models choroideremia (CHM), an X-linked chorioretinal dystrophy, which predominantly affects the photoreceptors, retinal pigment epithelium (RPE), and choroid. In this study, we examined the transcriptomic signature of the chmru848 zebrafish retina to reveal the upregulation of cytokine pathways and glia migration, upregulation of oxidative, ER stress and apoptosis markers, and the dysregulation of glucose metabolism with the downregulation of glycolysis and the upregulation of the oxidative phase of the pentose phosphate pathway. Glucose uptake was impaired in the chmru848 retina using the 2-NBDG glucose uptake assay. Following the overexpression of human PFKM, partial rescue was seen with the preservation of photoreceptors and RPE and increased glucose uptake, but without modifying glycolysis and oxidative stress markers. Therapies targeting glucose metabolism in CHM may represent a potential remedial approach
Incidence of diabetes mellitus following hospitalisation for COVID-19 in the United Kingdom: A prospective observational study
No full textBackground: People hospitalised for coronavirus disease 2019 (COVID-19) have elevated incidence of diabetes. However, it is unclear whether this is due to shared risk factors, confounding or stress hyperglycaemia in response to acute illness. Methods: We analysed a multicentre prospective cohort study (PHOSP-COVID) of people ≥18 years discharged from NHS hospitals across the United Kingdom following COVID-19. Individuals were included if they attended at least one research visit with a HbA1c measurement within 14 months of discharge and had no history of diabetes at baseline. The primary outcome was new onset diabetes (any type), as defined by a first glycated haemoglobin (HbA1c) measurement ≥6.5% (≥48 mmol/mol). Follow-up was censored at the last HbA1c measurement. Age-standardised incidence rates and incidence rate ratios (adjusted for age, sex, ethnicity, length of hospital stay, body mass index, smoking, physical activity, deprivation, hypertension, hyperlipidaemia/hypercholesterolaemia, intensive therapy unit admission, invasive mechanical ventilation, corticosteroid use and C-reactive protein score) were calculated using Poisson regression. Incidence rates were compared with the control groups of published clinical trials in the United Kingdom by applying the same inclusion and exclusion criteria, where possible. Results: Incidence of diabetes was 91.4 per 1000 person-years and was higher in South Asian (incidence rate ratios [IRR] = 3.60; 1.77, 7.32; p < 0.001) and Black ethnic groups (IRR = 2.36; 1.07, 5.21; p = 0.03) compared with White ethnic groups. When restricted to similar characteristics, the incidence rates were similar to those in UK clinical trials data. Conclusion: Diabetes incidence following hospitalisation for COVID-19 is high, but it remains uncertain whether it is disproportionately higher than pre-pandemic levels
HIV PrEP programmes as a framework for diagnosing and treating HBV infection in adolescents and young adults in KwaZulu-Natal, South Africa
No full textBackground
Guidelines for Hepatitis B treatment released by the World Health Organization in 2024 include the potential for use of dual therapy, combining tenofovir with either emtricitabine or lamivudine. These fixed-dose combinations are also used for Pre-Exposure Prophylaxis (PrEP) in people at risk of Human Immunodeficiency Virus (HIV). We hypothesize that pre-existing HIV PrEP programmes can support access to HBV testing and treatment
Methods
At the Africa Health Research Institute (AHRI) in KwaZulu Natal, South Africa, we evaluated PrEP uptake and retention amongst adolescents and young adults aged 15-30 years. We reviewed HBV status, acceptance of PrEP and retention in follow-up between June 2022 - Sept 2024.
Results
15,847 adolescents and young adults received an assessment in the community, of whom 3481/15847 (21.9%) were eligible for HIV prevention interventions. 3431/3481 (98.6%) accepted HBV screening, of whom 21/3431 (0.6%) tested positive for HBsAg. These 21 individuals had not previously been aware of their HBV status, but one was already on antiretroviral therapy for HIV infection. Amongst the remaining 20, 16/20 (80%) were considered eligible for PrEP, and 15 started PrEP. When investigating follow up and retention in care, among 15 individuals due for a refill 8/15 (53.3%) returned at least once.
Conclusion
Sexual reproductive health and PrEP programmes provide an opportunity for HBV testing and treatment. However, attrition from the care cascade at each step highlights the pressing need for interventions that address barriers to sustainable delivery of long-term care
Uveal Melanoma UK national guidelines: 2023 update.
No full textUK Guidelines for the management of uveal melanoma (UM) were first published in 2015 using an evidence-based systematic approach. The primary aim of this guideline was to optimise patient care by providing recommendations based on the best available scientific evidence. The resulting guideline reflected the strengths and weaknesses of the available evidence, made recommendations that were clinically impactful around prognostication, surveillance, and treatment for patients with primary lesions and metastatic disease. The guideline development process and content met the standards required by NICE and were ultimately NICE accredited. Here, we present an update to these guidelines, highlighting where practice or treatment has changed to such an extent that the original recommendations are now out of date. Presented here are updated guidelines on molecular and genetic testing, management of metastatic disease and clinical surveillance
Gene network organization, mutation, and selection collectively drive developmental pattern evolvability and predictability
No full textA hallmark of development is the generation of spatial patterns driven by morphogen gradients and gene regulatory networks (GRNs). Although the mechanistic basis by which GRNs orchestrate cellular responses and tissue patterning during development is well understood, their evolutionary dynamics remain less clear. Still, mutations in regulatory elements that govern GRN-driven patterning are a key mechanism for patterning evolution. In this study, we use the evolution of a stripe phenotype as a model framework to investigate the evolutionary dynamics associated with the emergence of new spatial gene expression boundaries and the adjustment of existing boundaries. To probe general principles of GRN-driven pattern evolution we introduce a new high-throughput theoretical framework that rapidly produces a comprehensive dataset of evolutionary trajectories. We leverage this large dataset to investigate the types of mutations that drive different phenotypic shifts in spatial patterning. Our findings suggest that the order in which mutations in gene-gene interactions appear and the specific combination of gene-gene interactions that mutate together determine the evolvability of novel spatial gene expression patterns. We interpret our results in the context of epistatic effects that naturally arise in networks of interconnected genes and show how contingencies and constraints emerge in our system. Our results elucidate the interplay between mutation and gene network organization, revealing how historical contingencies arise and impact the evolvability of GRNs and the predictability of their evolutionary outcomes
ATG9A and ARFIP2 cooperate to control PI4P levels for lysosomal repair.
No full textLysosome damage activates multiple pathways to prevent lysosome-dependent cell death, including a repair mechanism involving endoplasmic reticulum (ER)-lysosome membrane contact sites, phosphatidylinositol 4-kinase-2a (PI4K2A), phosphatidylinositol-4 phosphate (PI4P), and oxysterol-binding protein-like proteins (OSBPLs) lipid transfer proteins. PI4K2A localizes to the trans-Golgi network and endosomes, yet how it is delivered to damaged lysosomes remains unknown. During acute sterile damage and damage caused by intracellular bacteria, we show that ATG9A-containing vesicles perform a critical role in delivering PI4K2A to damaged lysosomes. ADP ribosylation factor interacting protein 2 (ARFIP2), a component of ATG9A vesicles, binds and sequesters PI4P on lysosomes, balancing OSBPL-dependent lipid transfer and promoting the retrieval of ATG9A vesicles through the recruitment of the adaptor protein complex-3 (AP-3). Our results identify a role for mobilized ATG9A vesicles and ARFIP2 in lysosome homeostasis after damage and bacterial infection
Cholesterol pathway gene variants and reduced keratinocyte cholesterol support a final common druggable pathway in hyperproliferative inflammatory skin diseases.
No full textHyperproliferative inflammatory skin disease (HISD) is frequently seen in rare monogenic diseases of cholesterol metabolism and responds to topical cholesterol/statin. We hypothesised that aberrant cholesterol metabolism within keratinocytes could be important in HISD more generally, driven by either immunological or lipid pathway genetic variation. Whilst other epidermal lipids have been well characterised in HISDs, cholesterol and its metabolites have not. Using GCxGC 3D mass spectrometry we find here that primary keratinocytes from diverse monogenic HISDs (Inflammatory Linear Verruvous Epidermal Naevus ILVEN n=14, CHILD syndrome n=2), and from plaque psoriasis (n=2), demonstrate significantly reduced mean cholesterol across all patient groups compared to controls. This striking abnormality appears causally implicated, as treatment in vitro with cholesterol and statin rescues the cellular hyperproliferation. Using SNPsea and burden analysis of large international psoriasis cohorts we go on to show that GWAS hits are significantly enriched in proximity to genes encoding lipid metabolic pathways, and that rare variants in lipid metabolic pathway genes are significantly enriched in psoriasis patients. These data identify a final common pathway of aberrant keratinocyte cholesterol metabolism in HISD, which should be drugged topically to avoid first pass metabolism. In parallel we implicate genetic variation in lipid pathway genes in psoriasis susceptibility, potentially explaining the co-morbidity of abnormal serum lipid profile and psoriasis
Evaluating Cellpose SAM as a segmentation algorithm for downstream cell morphology analysis
No full text• It is known that exposing cells to chemicals can alter their morphology, for example Dimethyl Sulfoxide (DMSO) or Okadaic acid induceapoptosis, a programmed cell death characterised in part by cell membrane shrinkage and cytoplasm condensation [1].• To investigate the phenotypical changes of individual cells within a monolayer, the cell membranes need to be segmented.• Our aim was to optimise Cellpose SAM as a segmentation tool and to evaluate whether the morphological changes associated with cell death impact segmentation performance.• This was achieved by segmenting images of cell monolayers before and after treating them with an apoptosis inducing agent, henceforth known as ‘untreated’ and ‘treated’ images, respectively.Poster presented as part of the Crick BioImage Analysis Symposium 2025.Permission has been given by authors to upload to Crick Figshare. Copyright remains with the original authors.</p