The aim of this review is to summarize the current and emergent approaches to characterize the small intestinal microbiota and discuss the treatment options for management of small intestinal ...bacterial overgrowth (SIBO).
This review captures the growing body of evidence for the role of SIBO, a type of small intestinal dysbiosis in the pathophysiology various gastrointestinal and extraintestinal disorders. We have highlighted the drawbacks of the available methods for characterizing the small intestinal microbiota and focus on the new culture-independent techniques to diagnose SIBO. Although recurrence is common, targeted modulation of the gut microbiome as a therapeutic option for management of SIBO is associated with improvement in symptoms and quality of life.
As a first step to precisely characterize the potential link between SIBO and various disorders, we need to address the methodological limitations of the available traditional tests for diagnosing SIBO. There is an urgency to develop culture independent techniques that can be routinely used in clinical setting, that will enable characterization of the gastrointestinal microbiome and explore the response to antimicrobial therapy including the links between long-lasting symptom resolution and the microbiome.
To demonstrate a high-yield molecular diagnostic workflow for lateralized overgrowth (LO), a congenital condition with abnormal enlargement of body parts, and to classify it by molecular genetics.
We ...categorized 186 retrospective cases of LO diagnosed between 2003 and 2023 into suspected Beckwith-Wiedemann spectrum, PIK3CA-related overgrowth spectrum (PROS), vascular overgrowth, or isolated LO, based on initial clinical assessments, to determine the appropriate first-tier molecular tests and tissue for analysis. Patients underwent testing for 11p15 epigenetic abnormalities or somatic variants in genes related to PI3K/AKT/mTOR, vascular proliferation, and RAS-MAPK cascades using blood or skin DNA. For cases with negative initial tests, a sequential cascade molecular approach was employed to improve diagnostic yield.
This approach led to a molecular diagnosis in 54% of cases, 89% of cases consistent with initial clinical suspicions, and 11% reclassified. Beckwith-Wiedemann spectrum was the most common cause, with 43% of cases exhibiting 11p15 abnormalities. PIK3CA-related overgrowth spectrum had the highest confirmation rate, with 74% of clinically diagnosed patients showing a PIK3CA variant. Vascular overgrowth demonstrated significant clinical overlap with other syndromes. A molecular diagnosis of isolated LO proved challenging, with only 21% of cases classifiable into a specific condition.
LO is underdiagnosed from a molecular viewpoint and to date has had no diagnostic guidelines, which is crucial for addressing potential cancer predisposition, enabling precision medicine treatments, and guiding management. This study sheds light on the molecular etiology of LO, highlighting the importance of a tailored diagnostic approach and of selecting appropriate testing to achieve the highest diagnostic yield.
Drug-induced gingival overgrowth (DIGO) is one of the side effects produced by therapeutic agents, most commonly phenytoin, nifedipine and cyclosporin A. However, the precise mechanism of DIGO is not ...entirely understood. A literature search of the MEDLINE/PubMed databases was conducted to identify the mechanisms involved in DIGO. The available information suggests that the pathogenesis of DIGO is multifactorial, but common pathogenic sequelae of events emerge, i.e., sodium and calcium channel antagonism or disturbed intracellular handling of calcium, which finally lead to reductions in intracellular folic acid levels. Disturbed cellular functions, mainly in keratinocytes and fibroblasts, result in increased collagen and glycosaminoglycans accumulation in the extracellular matrix. Dysregulation of collagenase activity, as well as integrins and membrane receptors, are key mechanisms of reduced degradation or excessive synthesis of connective tissue components. This manuscript describes the cellular and molecular factors involved in the epithelial-mesenchymal transition and extracellular matrix remodeling triggered by agents producing DIGO.
Overgrowth syndromes are characterized by global or localized disproportionate growth associated with other anomalies, including vascular malformations and neurological and/or visceral disorders. ...CLOVES (Congenital Lipomatous asymmetric Overgrowth of the trunk with lymphatic, capillary, venous, and combined‐type Vascular malformations, Epidermal naevi, Scoliosis/Skeletal and spinal anomalies) is an overgrowth syndrome caused by mosaic activating mutation in gene PIK3CA, which gives rise to abnormal PI3K‐AKT‐mTOR pathway activation. These mutations are responsible for the clinical manifestations of the syndrome, which include low‐ and high‐flow vascular malformations, thoracic lipomatous hyperplasia, asymmetric growth, and visceral and neurological disorders. These common anomalies are illustrated with figures from two personal cases. Identification of the clinical and genetic characteristics of CLOVES syndrome is crucial for the differential diagnosis with other overgrowth syndromes, such as Proteus or Klippel–Trenaunay (K–T) syndromes, and for the therapeutic management of the different anomalies. In this context, a new entity comprising different syndromes with phenotypic mutations in PIK3CA has been proposed, designated PIK3CA‐related overgrowth spectrum (PROS), with the aim of facilitating clinical management and establishing appropriate genetic study criteria.
PIK3CA pathway and syndromes. Left asymmetric overgrowth and sandal gap.
Vascular malformations syndromes: an update Martinez-Lopez, Antonio; Salvador-Rodriguez, Luis; Montero-Vilchez, Trinidad ...
Current opinion in pediatrics,
12/2019, Letnik:
31, Številka:
6
Journal Article
Recenzirano
To provide an update of vascular malformation syndromes by reviewing the most recent articles on the topic and following the new International Society for the Study of Vascular Anomalies (ISSVA) 2018 ...classification.
This review discusses the main features and diagnostic approaches of the vascular malformation syndromes, the new genetic findings and the new therapeutic strategies developed in recent months.
Some vascular malformations can be associated with other anomalies, such as tissue overgrowth. PIK3CA-related overgrowth spectrum (PROS) is a group of rare genetic disorders with asymmetric overgrowth caused by somatic mosaic mutations in PI3K-AKT-mTOR pathway that encompass a heterogeneous group of rare disorder that are associated with the appearance of overgrowth. CLOVES syndrome and Klippel-Trénaunay syndrome are PROS disease. Proteus syndrome is an overgrowth syndrome caused by a somatic activating mutation in AKT1. CLOVES, Klippel-Trénaunay and Proteus syndromes are associated with high risk of thrombosis and pulmonary embolism. Hereditary hemorrhagic telangiectasia is an autosomic dominant disorder characterized by the presence of arteriovenous malformations. New therapeutic strategies with bevacizumab and thalidomide have been employed with promising results.
The EZH2, EED, and SUZ12 genes encode proteins that comprise core components of the polycomb repressive complex 2 (PRC2), an epigenetic "writer" with H3K27 methyltransferase activity, catalyzing the ...addition of up to three methyl groups on histone 3 at lysine residue 27 (H3K27). Partial loss-of-function variants in genes encoding the EZH2 and EED subunits of the complex lead to overgrowth, macrocephaly, advanced bone age, variable intellectual disability, and distinctive facial features. EZH2-associated overgrowth, caused by constitutional heterozygous mutations within Enhancer of Zeste homologue 2 (EZH2), has a phenotypic spectrum ranging from tall stature without obvious intellectual disability or dysmorphic features to classical Weaver syndrome (OMIM #277590). EED-associated overgrowth (Cohen-Gibson syndrome; OMIM #617561) is caused by germline heterozygous mutations in Embryonic Ectoderm Development (EED), and manifests overgrowth and intellectual disability (OGID), along with other features similar to Weaver syndrome. Most recently, rare coding variants in SUZ12 have also been described that present with clinical characteristics similar to the previous two syndromes. Here we review the PRC2 complex and clinical syndromes of OGID associated with core components EZH2, EED, and SUZ12.
Objective
We investigated the importance of reactive oxygen species (ROS) on developing gingival overgrowth (GO) and then introduced the antioxidant strategy to prevent, or even reduce GO.
Background
...Gingival overgrowth is a common side effect of the patients receiving cyclosporine A (CsA), an immune suppressant. Although it has been broadly investigated, the exact pathogenesis of the induced GO is still uncertain.
Methods
We cultured human primary gingival fibroblasts and used animal model of GO to investigate the ameliorative effects of antioxidants on CsA‐induced GO. To examine the CsA‐induced oxidative stress, associated genes and protein expression, and the overgrown gingiva of rats by using immunocytochemistry, confocal laser scanning microscopy, real‐time PCR, ELISA, gelatin zymography, gingival morphological, and immunohistochemical analysis.
Results
We found for the first time that ROS was responsible for the CsA‐induced oxidative stress and TGF‐β1 expression in human primary gingival fibroblasts, as well as the GO of rats. The antioxidants (oxidative scavenger of vitamin E and an antioxidative enzyme inducer of hemin) ameliorated CsA‐induced pathological and morphological alterations of GO without affected the CsA‐suppressed il‐2 expression in rats. CsA‐induced oxidative stress, HO‐1, TGF‐β1, and type II EMT were also rescued by antioxidants treatment.
Conclusions
We concluded that CsA repetitively stimulating the production of ROS is the cause of CsA‐GO which is ameliorated by treating antioxidants, including vitamin E and sulforaphane. Furthermore, the immunosuppressive effect of CsA is not interfered by antioxidant treatments in rats. This finding may thus help the clinician devise better prevention strategies in patients susceptible to GO.
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