Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Tatton-Brown-Rahman overgrowth syndrome. Core disease mechanisms, molecula...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 19
• Snippets retrieved: 20

Relevant Papers

[1] Molecular mechanisms of human overgrowth and use of omics in its diagnostics: chances and challenges

• Authors: Dirk Prawitt, Thomas Eggermann
• Year: 2024
• Venue: Frontiers in Genetics
• URL: https://www.semanticscholar.org/paper/23d333d69235a7becab3d3375dfd417f9e2d4fc5
• DOI: 10.3389/fgene.2024.1382371
• PMID: 38894719
• PMCID: 11183334
• Citations: 5
• Summary: Physicians should consider molecular genetic testing as a first diagnostic step in overgrowth syndromes, as the urgent need for a precise diagnosis in tumor predisposition syndromes has to be taken into account as the basis for an early monitoring and therapy.
• Evidence snippets:
• Snippet 1 (score: 0.504) > Overgrowth disorders comprise a group of entities with a variable phenotypic spectrum ranging from tall stature to isolated or lateralized overgrowth of body parts and or organs. Depending on the underlying physiological pathway affected by pathogenic genetic alterations, overgrowth syndromes are associated with a broad spectrum of neoplasia predisposition, (cardio) vascular and neurodevelopmental anomalies, and dysmorphisms. Pathologic overgrowth may be of prenatal or postnatal onset. It either results from an increased number of cells (intrinsic cellular hyperplasia), hypertrophy of the normal number of cells, an increase in interstitial spaces, or from a combination of all of these. The underlying molecular causes comprise a growing number of genetic alterations affecting skeletal growth and Growth-relevant signaling cascades as major effectors, and they can affect the whole body or parts of it (mosaicism). Furthermore, epigenetic modifications play a critical role in the manifestation of some overgrowth diseases. The diagnosis of overgrowth syndromes as the prerequisite of a personalized clinical management can be challenging, due to their clinical and molecular heterogeneity. Physicians should consider molecular genetic testing as a first diagnostic step in overgrowth syndromes. In particular, the urgent need for a precise diagnosis in tumor predisposition syndromes has to be taken into account as the basis for an early monitoring and therapy. With the (future) implementation of next-generation sequencing approaches and further omic technologies, clinical diagnoses can not only be verified, but they also confirm the clinical and molecular spectrum of overgrowth disorders, including unexpected findings and identification of atypical cases. However, the limitations of the applied assays have to be considered, for each of the disorders of interest, the spectrum of possible types of genomic variants has to be considered as they might require different methodological strategies. Additionally, the integration of artificial intelligence (AI) in diagnostic workflows significantly contribute to the phenotype-driven selection and interpretation of molecular and physiological data.
• Snippet 2 (score: 0.421) > The molecular diagnostic analyses encompass DNA-, epigenetic-and transcriptomic-analyses that all have been increasingly developed during the last years (compare Figure 2).They have progressed from a single disease-gene sequencing to whole genome/exome/transcriptome sequencing approaches.These omic strategies can confirm a clinical diagnosis with the use of a broad, rather unfocused approach, but thus also produce quite a number of unsolicited findings, or variants of unknown significance (VUS).AI-based integrated methods will help to reclassify VUS according to their relevance for disease and ultimately detect molecular signatures of the overgrowth syndromes.This could also help to uncover trans-acting factors, e.g., for epigenetic trans-regulations (Eggermann et al., 2022) or gene-networks, like the Imprinted-Gene-Network (IGN) (Varrault et al., 2006;Eggermann et al., 2021).The plethora of information in omics data can thus be used to bioinformatically gain deeper insight into relevant genomic background effects.Examples are mutations in the EZH2 (Weaver syndrome) and DNMT3A (Tatton-Brown-Rahman syndrome) which cause overgrowth, but are also candidates for the Facioscapulohumeral Dystrophy (FSHD) with a wide heterogeneity of disease, complicating FSHD diagnosis and the genotype-phenotype correlation among patients and within families.A recent study applied Whole Exome Sequencing (WES) to investigate known and unknown genetic contributors that may be involved in FSHD and may represent potential disease modifiers.The WES data analysis suggests that different genes can contribute to disease heterogeneity in presence of a FSHD permissive (genetic) background (Strafella et al., 2023).Similar strategies could be used to analyze overgrowth syndromes with causative genetic mutations.A combined segregation analyses for genetic variants in family members together with clinical findings and a methylation analysis probably will help to establish a reliable genotypephenotype correlation of the complex overgrowth-syndromes.

[2] PRC2 functions in development and congenital disorders

• Authors: Orla Deevy, A. Bracken
• Year: 2019
• Venue: Development (Cambridge, England)
• URL: https://www.semanticscholar.org/paper/74a506997c5e6926f6faa584354da34fbc91688d
• DOI: 10.1242/dev.181354
• PMID: 31575610
• PMCID: 6803372
• Citations: 104
• Influential citations: 2
• Summary: A model in which the dysregulation of these modifications at intergenic regions is a shared molecular feature of genetically distinct but highly phenotypically similar overgrowth syndromes in humans is proposed.
• Evidence snippets:
• Snippet 1 (score: 0.465) > Here, we have proposed a new molecular viewpoint from which the phenotypic overlap between the genetically distinct Weaver, Sotos and Tatton-Brown-Rahman overgrowth syndromes may be understood. We speculate that aberrations in the crosstalk between PRC2, NSD1 and DNMT3A, and an imbalance in their associated modifications at intergenic chromatin, might be a key shared feature of these distinct, but related, developmental disorders. However, experimental testing of this hypothesis will be required. To this end, future studies seeking to characterise the molecular aetiology of Weaver, Sotos or Tatton-Brown-Rahman syndrome could widen their scope to incorporate analyses of H3K27me2, H3K36me2 and DNA methylation. The study of DNA methylation patterns in these disorders is likely to be of particular clinical value. DNA methylation profiling is already in use as a diagnostic tool for various cancers, and it holds promise as a method to discriminate between the clinically overlapping Weaver, Sotos and Tatton-Brown-Rahman syndromes at the molecular level. Future analyses of the enzymatic activities of mutant forms of core PRC2 members should also be refined to delineate between the ability to mediate H3K27me3, H3K27me2 and H3K27me1, and genomic profiling of cells from patients should be extended to look for alterations in the deposition of these modifications at intergenic chromatin. > To date, mouse models of Weaver, Sotos and Tatton-Brown-Rahman syndrome are limited. Assuming loss of function as the primary mutational mechanism of disease, it is striking that no growth-related phenotypes have been reported for heterozygous lossof-function Ezh2, Eed, Suz12, Nsd1 or Dnmt3a mutant mice (Table 1). This may simply be a reporting issue, as developmental overgrowth phenotypes can be relatively mild in mice and therefore can easily go unnoticed by a researcher who is more focussed on the homozygous condition and/or is not explicitly searching for subtle growth-associated phenotypes. Another possibility is that the assumption of a simple loss-of-function mutational mechanism may be incorrect. Alternative

[3] Lateralized and Segmental Overgrowth in Children

• Authors: A. Mussa, D. Carli, S. Cardaropoli, G. Ferrero, N. Resta
• Year: 2021
• Venue: Cancers
• URL: https://www.semanticscholar.org/paper/1bf068188ceb52b6d570aedc7fc2b9bdfd8c7ca9
• DOI: 10.3390/cancers13246166
• PMID: 34944785
• PMCID: 8699773
• Citations: 19
• Summary: Interestingly, some LO shares molecular mechanisms with cancer: recent advances in tumor biological pathway druggability and growth downregulation offer new avenues for the treatment of the most severe and complicated LO.
• Evidence snippets:
• Snippet 1 (score: 0.404) > Simple Summary Congenital lateralized or segmental overgrowth (LO) disorders are conditions characterized by excessive tissue growth of a body region often associated with a predisposition to cancer. LOs are caused by mosaic DNA anomalies, that is, they are present only in a part of the cells making up the body. LOs have an extremely heterogeneous clinical presentation: they widely overlap in presentation, are difficult to frame from a clinical point of view and have a diagnostic complexity representing a challenge for the clinician who approaches them. Here we review the key features of the various LOs, expose their molecular causes, and detail the implications for each of them, such as the need for specific cancer screening or the possibility of treatment. The latter represents a recent scientific achievement in medicine, allowed by the development of precision drugs finely tuning cellular pathways involved in growth and tumorigenesis deranged in LO. Abstract Congenital disorders of lateralized or segmental overgrowth (LO) are heterogeneous conditions with increased tissue growth in a body region. LO can affect every region, be localized or extensive, involve one or several embryonic tissues, showing variable severity, from mild forms with minor body asymmetry to severe ones with progressive tissue growth and related relevant complications. Recently, next-generation sequencing approaches have increased the knowledge on the molecular defects in LO, allowing classifying them based on the deranged cellular signaling pathway. LO is caused by either genetic or epigenetic somatic anomalies affecting cell proliferation. Most LOs are classifiable in the Beckwith–Wiedemann spectrum (BWSp), PI3KCA/AKT-related overgrowth spectrum (PROS/AROS), mosaic RASopathies, PTEN Hamartoma Tumor Syndrome, mosaic activating variants in angiogenesis pathways, and isolated LO (ILO). These disorders overlap over common phenotypes, making their appraisal and distinction challenging. The latter is crucial, as specific management strategies are key: some LO is associated with increased cancer risk making imperative tumor screening since childhood. Interestingly, some LO shares molecular mechanisms with cancer: recent advances in tumor biological pathway druggability and growth downregulation offer new avenues for the treatment of the most severe and complicated LO.

[4] Differential Diagnoses of Overgrowth Syndromes: The Most Important Clinical and Radiological Disease Manifestations

• Authors: L. S. Lacerda, Ú. Alves, J. F. Zanier, D. C. Machado, G. B. Camilo et al.
• Year: 2014
• Venue: Radiology Research and Practice
• URL: https://www.semanticscholar.org/paper/fd1aacd0cc2676d4db591d32a211f3cd35ebe9ae
• DOI: 10.1155/2014/947451
• PMID: 25009745
• PMCID: 4070411
• Citations: 38
• Summary: In the current review, four overgrowth syndromes were characterized (Proteus syndrome, Klippel-Trenaunay-Weber syndrome, Madelung's disease, and neurofibromatosis type I) and illustrated using cases from the authors' institution.
• Evidence snippets:
• Snippet 1 (score: 0.391) > Functional studies demonstrated that underexpression of the DIS3L2 gene was associated with cellular growth enhancement [14]. > Several classifications have been developed in an attempt to facilitate the diagnosis of these syndromes, but these attempts have been hindered by the syndromes' several overlapping clinical manifestations [1,15]. Neylon et al. [2] proposed a classification of overgrowth syndromes by ordering them according to their typical timing of clinical presentation as follows: (a) syndromes exhibiting overgrowth in the neonatal period, including Beckwith-Wiedemann syndrome, Sotos syndrome, Weaver syndrome, and Perlman syndrome and (b) overgrowth syndromes usually identified in childhood, including Klinefelter syndrome and Proteus syndrome. Major progress such as the identification of genetic causes has recently enhanced the knowledge of the underlying pathophysiological mechanisms, the delineation of the genotype-phenotype relationships, and the establishment of the main characteristics for each condition [1]. As a consequence, the possibilities for distinguishing between different overgrowth syndromes have increased. Several studies are currently underway to organize these types of disorders according to a molecular classification system for overgrowth syndromes in order to assist the practicing clinician [16][17][18]. Radiological abnormalities are increasingly important for the clinical differentiation between overgrowth syndromes, making those abnormalities valuable diagnostic criteria for some of these conditions. > In this review, four overgrowth syndromes-Proteus syndrome, Klippel-Trenaunay-Weber syndrome, Madelung's disease, and neurofibromatosis type I-are described. The main clinical and imaging features these syndromes are highlighted using clinical cases evaluated in our institution. Although they are not the most common overgrowth syndromes, manifestations of these four syndromes overlap with other more prevalent overgrowth syndromes. Thus, it is of interest to present these cases which were diagnosed from the suspicion caused by imaging findings.

[5] Epigenetic Mechanisms of Obesity: Insights from Transgenic Animal Models

• Authors: E. Na
• Year: 2025
• Venue: Life
• URL: https://www.semanticscholar.org/paper/d5b9cf7146a9c5672c444d2b45d38def03a52e87
• DOI: 10.3390/life15040653
• PMID: 40283207
• PMCID: 12028693
• Citations: 2
• Summary: The role of epigenetic mechanisms in obesity is explored, emphasizing insights from transgenic animal models and clinical studies, and the evolution of obesity research from homeostatic to allostatic frameworks is discussed, highlighting key neuroendocrine regulators of energy balance.
• Evidence snippets:
• Snippet 1 (score: 0.387) > These clinical data suggest that central epigenetic mechanisms are influenced by obesogenic diets and may contribute to obese pathology. > Alterations in methylation status are mediated by DNMTs and mutations in the genes that encode for these enzymes may be another candidate epigenetic mechanism underlying the etiology of obesity. For example, mutations in DNMT3a lead to the development of a rare disorder known as Tatton-Brown-Rahman Syndrome (TBRS), which is marked by symptoms of intellectual disability, height and head circumference overgrowth, and obesity [156,157]. A transgenic mouse model of TBRS, in which DNMT3a was constitutively knocked out, recapitulated the obese phenotype and hyperphagia while exposed to either a regular or high-fat diet [158,159]. > These data collectively suggest a significant link between epigenetic mechanisms and obesity pathogenesis. The caveat to these clinical findings, however, is the paucity of data linking changes to the epigenome at the central level, experiments that may be more amenable to animal models. Data from transgenic animal models have brought significant insight into neuroepigenetic mechanisms affected by environmental factors such as obesogenic diet. Bridging the conceptual gap between human clinical studies and animal research is the next critical step to identifying neuroepigenetic factors that underlie the pathophysiology of obesity. The effects of UPFs on our epigenomes are insufficient at this time and more work is needed to determine the cumulative effects UPFs have on body energy regulatory mechanisms. The insights provided by such research could be key to unlocking the mystery of the precipitous rise in and enduring effects of obesity.

[6] The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

• Authors: D. Martinelli, D. Diodato, Emanuela Ponzi, M. Monné, S. Boenzi et al.
• Year: 2015
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/ed033868ee677da141e5c926bc7c93cac242ea06
• DOI: 10.1186/s13023-015-0242-9
• PMID: 25874378
• PMCID: 4358699
• Citations: 92
• Influential citations: 5
• Summary: The clinical phenotype of HHH syndrome is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.
• Evidence snippets:
• Snippet 1 (score: 0.378) > Although the disease responds well to treatment with low risk of relapse of hyperammonemia [38], slowly progressive pyramidal signs characterize the chronic course, as also seen in argininemia [89]. However, the mechanism(s) of pyramidal dysfunction in HHH syndrome still remains to be elucidated. Creatine deficiency may contribute to the pathogenetic mechanism of the syndrome, as creatine is relevant for mitochondrial energy metabolism, regulation of glycolysis, proteins synthesis, membrane stabilization and neuromodulation [77,78,85]. This could be in line with the finding of abnormally shaped mitochondria at electron microscopy studies in skin fibroblasts, hepatocytes and muscle biopsy from HHH syndrome patients [11,23,82]. Furthermore, a mitochondrial dysfunction has been recently related to the effects of ornithine and homocitrulline in causing oxidative stress and disturbed mitochondrial homeostasis [79,80]. > A further mechanism that can be involved in the pathophysiology of HHH syndrome is related to polyamines metabolism. Shimizu and colleagues reported increased total and fractional (putrescine, cadaverine, spermine, spermidine) polyamines in one HHH syndrome patient [30]. Indeed, the clinical similarities between HHH syndrome and argininemia, which has been associated to an abnormal polyamine metabolism [91,92], may suggest a common pathogenetic mechanism causing pyramidal dysfunction. > Overall, the pathogenesis of HHH syndrome is complex and not completely understood. It is likely that different mechanisms, including the impact of low mitochondrial ornithine on UC flux, the presence of hyperammonemic crises and the disturbance of other pathways in major organs play a role in determining the heterogeneous clinical presentation of ORC1 deficiency. > In addition, as molecular studies failed to disclose a correlation between type of mutations or ornithine transport capacity and disease severity, an effect of genetic modifiers, such as ORC genes redundancy, seems to be likely, but further studies are certainly needed to clarify this point.

[7] Gingival fibromatosis: clinical, molecular and therapeutic issues

• Authors: K. Gawron, K. Łazarz-Bartyzel, J. Potempa, M. Chomyszyn-Gajewska
• Year: 2016
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/496c88f34ce1b2c5c46f8d30e4f75792c9f00d00
• DOI: 10.1186/s13023-016-0395-1
• PMID: 26818898
• PMCID: 4729029
• Citations: 95
• Influential citations: 7
• Summary: Treatments vary according to the type of overgrowth and the extent of disease progression, thus, scaling of teeth is sufficient in mild cases, while in severe cases surgical intervention is required.
• Evidence snippets:
• Snippet 1 (score: 0.376) > Gingival fibromatosis is a rare and heterogeneous group of disorders that develop as slowly progressive, local or diffuse enlargements within marginal and attached gingiva or interdental papilla. In severe cases, the excess tissue may cover the crowns of the teeth, thus causing functional, esthetic, and periodontal problems, such as bone loss and bleeding, due to the presence of pseudopockets and plaque accumulation. It affects both genders equally. Hereditary, drug-induced, and idiopathic gingival overgrowth have been reported. Hereditary gingival fibromatosis can occur as an isolated condition or as part of a genetic syndrome. The pathologic manifestation of gingival fibromatosis comprises excessive accumulation of extracellular matrix proteins, of which collagen type I is the most prominent example. Mutation in the Son-of-Sevenless-1 gene has been suggested as one possible etiological cause of isolated (non-syndromic) hereditary gingival fibromatosis, but mutations in other genes are also likely to be involved, given the heterogeneity of this condition. The most attractive concept of mechanism for drug-induced gingival overgrowth is epithelial-to-mesenchymal transition, a process in which interactions between gingival cells and the extracellular matrix are weakened as epithelial cells transdifferentiate into fibrogenic fibroblast-like cells. The diagnosis is mainly made on the basis of the patient’s history and clinical features, and on histopathological evaluation of affected gingiva. Early diagnosis is important, mostly to exclude oral malignancy. Differential diagnosis comprises all pathologies in the mouth with excessive gingival overgrowth. Hereditary gingival fibromatosis may present as an autosomal-dominant or less commonly autosomal-recessive mode of inheritance. If a systemic disease or syndrome is suspected, the patient is directed to a geneticist for additional clinical examination and specialized diagnostic tests. Treatments vary according to the type of overgrowth and the extent of disease progression, thus, scaling of teeth is sufficient in mild cases, while in severe cases surgical intervention is required. Prognosis is precarious and the risk of recurrence exists.

[8] A Rare Case of an Asymmetric Overgrowth Syndrome in a Kenyan African Child: A Case Report and Review of Literature

• Authors: Diana A Okello, Joseph Mutio, M. Masiga, S. Guthua, N. Kariuki et al.
• Year: 2022
• Venue: Cureus
• URL: https://www.semanticscholar.org/paper/8d0ff7feb9cba1e73a28bb999716a2143bf90370
• DOI: 10.7759/cureus.29761
• PMID: 36324351
• PMCID: 9617656
• Citations: 3
• Summary: A seven-year-old African male with progressive, asymmetric, postnatal overgrowth of the left side of his face and left upper limb is presented, highlighting the diagnosis of proteus syndrome.
• Evidence snippets:
• Snippet 1 (score: 0.375) > It is imperative to diagnose individuals with overgrowth syndromes for purposes of accurate genetic counselling, cancer surveillance, and overall prognosis [1]. > The patient presented with general and several specific features of PS [4,12]. These features included cerebriform connective tissue nevus and asymmetric disproportionate overgrowth of the left upper limb, left external auditory meatus, and spleen. Additionally, he had lymphangiomas, cystic lesions, lipomas, dolichocephaly, down-slanting palpebral fissures with ptosis, and a flattened nasal bridge. The patient's clinical presentation fits the clinical criteria for diagnosis of PS, as an asymmetric overgrowth syndrome that is progressive and typically noted in childhood, as presented in Figure 7 [4, 10,12,14,15]. Phenotypic presentations are induced by individual genes or different genes can produce one phenotype [16]. > The genesis of PS is AKT1 gene variation (c.49G>A, p. Glu17Lys) [6]. The patient had a peripheral blood sequence analysis and deletion/duplication panel testing which did not elicit this variation. However, from the literature, diagnosis of PS from peripheral blood DNA analysis is achieved in only 5% of confirmed cases. > A punch biopsy of the affected area, which was not approved by the parents, would offer a more definitive diagnosis [6]. > The management of patients with overgrowth syndromes such as PS is challenging and requires a multidisciplinary team owing to the varied clinical presentation and risk factors [11]. Current treatment does not modify the disease progression and is, therefore, symptom-oriented [17]. Keppler-Noreuil et al. confirmed that individuals with PS have an increased risk of fatal thromboembolic events, though the underlying mechanism remains unknown [18,19]. This may occur due to vascular malformations resulting in stasis and an abnormal hypercoagulable panel characterized by deficiencies in anti-thrombin III and Protein C or S [18].

[9] Precision Therapeutics in Lennox–Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy

• Authors: Debopam Samanta
• Year: 2025
• Venue: Children
• URL: https://www.semanticscholar.org/paper/455479c1bfbea7b90b73c109228f67c813d13888
• DOI: 10.3390/children12040481
• PMID: 40310132
• PMCID: 12025602
• Citations: 19
• Influential citations: 1
• Summary: A narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies, receptor and ligand dysfunction, receptor and ligand dysfunction, cell signaling abnormalities, cell signaling abnormalities, synaptopathies, and the repurposing of existing medications with mechanism-specific effects.
• Evidence snippets:
• Snippet 1 (score: 0.369) > Lennox–Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Current treatments primarily focus on symptom management through antiseizure medications (ASMs), dietary therapy, epilepsy surgery, and neuromodulation, but often fail to address the underlying pathophysiology or improve cognitive outcomes. As genetic causes are identified in 30–40% of LGS cases, precision therapeutics targeting specific molecular mechanisms are emerging as promising disease-modifying approaches. This narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies (SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1A), receptor and ligand dysfunction (GABA/glutamate systems), cell signaling abnormalities (mTOR pathway), synaptopathies (STXBP1, IQSEC2, DNM1), epigenetic dysregulation (CHD2), and CDKL5 deficiency disorder. Treatment modalities discussed include traditional ASMs, dietary therapy, targeted pharmacotherapy, antisense oligonucleotides, gene therapy, and the repurposing of existing medications with mechanism-specific effects. Early intervention with precision therapeutics may not only improve seizure control but could also potentially prevent progression to LGS in susceptible populations. Future directions include developing computable phenotypes for accurate diagnosis, refining molecular subgrouping, enhancing drug development, advancing gene-based therapies, personalizing neuromodulation, implementing adaptive clinical trial designs, and ensuring equitable access to precision therapeutic approaches. While significant challenges remain, integrating biological insights with innovative clinical strategies offers new hope for transforming LGS treatment from symptomatic management to targeted disease modification.

[10] Future research trends in understanding the mechanisms underlying allergic diseases for improved patient care

• Authors: H. Breiteneder, Z. Diamant, T. Eiwegger, W. Fokkens, C. Traidl‐Hoffmann et al.
• Year: 2019
• Venue: Allergy
• URL: https://www.semanticscholar.org/paper/e19b0755c4f4903f68377333676edebf9bd73c89
• DOI: 10.1111/all.13851
• PMID: 31056763
• PMCID: 6973012
• Citations: 90
• Influential citations: 3
• Summary: Recent developments in research and patient care and future trends in the discipline are reviewed and topics on food allergy, biologics, small molecules, and novel therapeutic concepts in allergen‐specific immunotherapy for airway disease are highlighted.
• Evidence snippets:
• Snippet 1 (score: 0.368) > The past decades have witnessed extensive progress in unraveling cellular and molecular mechanisms of immune regulation in asthma, allergic diseases, organ transplantation, autoimmune diseases, tumor biology, and chronic infections. 1,2 Consequently, a better understanding of the functions, the reciprocal regulation, and the counterbalance of subsets of immune and inflammatory cells but also structural cells-for example, epithelial and vascular cells, airway smooth muscle cells, neuroendocrine system-that interact via various intercellular messengers will indicate avenues for immune interventions and novel treatment modalities of allergic diseases and immunological disorders. It is generally expected that drug development in the next decades will show a significant shift from chemicals to biologicals. > After more than 20 years without any breakthrough drug becoming available for patients, several disciplines including allergology are now experiencing extraordinary times with the recent licensing of several major biological drugs and novel allergen-specific immunotherapy (AIT) vaccines. Several biological modifiers of the immune response targeting intracellular messengers or their receptors have been developed to date. [3][4][5][6][7][8] In addition, a number of promising small molecule drugs and vaccines are in the development pipeline. [9][10][11] This new era is now calling for the development of biomarkers and phenoand endotyping of diseases for customized patient care, which is termed stratified medicine, precision medicine, or personalized medicine. 4 Distinguishing phenotypes of a complex disease covers the observable clinically relevant properties of the disease but does not show a direct relationship to disease etiology and pathophysiology. In a complex condition, such as asthma, different pathogenetic mechanisms can induce similar clinical manifestations; however, they may require different treatment approaches. 12,13 These pathophysiological mechanisms underlying disease subgroups are addressed by the term "endotype." [12][13][14] Classification of complex diseases based on the concept of endotypes provides advantages for epidemiological, genetic, and drug-related studies. Accurate endotyping by using reliable biomarkers reflects the natural history of the disease and aims to predict the response to (targeted) treatments. 15 Recent studies have focused on better understanding

[11] PIK3CA-Related Overgrowth Spectrum From Diagnosis to Targeted Therapy: A Case of CLOVES Syndrome Treated With Alpelisib

• Authors: Angelica Pagliazzi, T. Oranges, G. Traficante, C. Trapani, F. Facchini et al.
• Year: 2021
• Venue: Frontiers in Pediatrics
• URL: https://www.semanticscholar.org/paper/87f0c58656384da54a5ca2be34198f978f83eb1e
• DOI: 10.3389/fped.2021.732836
• PMID: 34568242
• PMCID: 8459713
• Citations: 44
• Influential citations: 1
• Summary: The effect of Alpelisib (BYL719), a specific inhibitor for the p110α subunit of PI3K, was shown in patients with PROS disorders who had severe or life-threatening complications and were not sensitive to any other treatment.
• Evidence snippets:
• Snippet 1 (score: 0.365) > The term PIK3CA-related overgrowth spectrum embraces an increasing number of phenotypes, that we were used to consider as distinct clinical entities. A clear categorization of vascular malformations with or without segmental overgrowth based solely on the clinic is not always feasible, given the overlap of some characteristics between different disorders. It would be much easier to group vascular anomalies on the basis of a shared molecular pathogenesis: the term PROS, in fact, includes those conditions caused by the presence of a mosaic gainof-function variant in the PIK3CA gene, which leads to an overactivity of the PI3K/AKT/mTOR pathway in the involved tissues. Therefore, achieving a molecular diagnosis is now even more relevant to choose the most appropriate therapy. Indeed, advance in the knowledge of the pathogenesis of segmental overgrowth syndromes and vascular malformations has also opened the path to consider a tailored pharmacological therapy for these conditions. The discovery that signaling pathways involved in oncogenesis and cancer progression are equally responsible of benign diseases, such as PROS disorders, has drawn attention to the possibility of use in these latter targeted molecules deriving from cancer scientific research. On the other hand, repurposing cancer therapies for treatment of vascular anomalies and segmental overgrowth syndrome has prompted scientists to revisit therapeutic approaches in cancer patients (12). Conventional therapeutic approaches, such as scleroembolization or surgical debulking procedures, are rarely curative in patients with vascular malformations and PROS disorders and are not devoid of risks of complications and recurrence. Since constitutive activation of the PI3K/AKT/mTOR pathway is a major cause of vascular anomalies and overgrowth syndromes, the use of mTOR inhibitors, such as Sirolimus, appeared as a good therapeutic strategy (4). Nevertheless, Sirolimus is a direct inhibitor of mTORC1, which is found at the end of the PI3K/AKT pathway: activation of mTORC1 is responsible for some but not all of the biological effects caused by PI3K gain-of-function.

[12] PI3K Signaling in Tissue Hyper-Proliferation: From Overgrowth Syndromes to Kidney Cysts

• Authors: M. C. De Santis, V. Sala, M. Martini, G. Ferrero, E. Hirsch
• Year: 2017
• Venue: Cancers
• URL: https://www.semanticscholar.org/paper/0aa1714174e9d73aa3b2a771d8898673c6bf7089
• DOI: 10.3390/cancers9040030
• PMID: 28353628
• PMCID: 5406705
• Citations: 38
• Influential citations: 1
• Summary: The most recent findings on how the same pathway may lead to different biological effects, due to the convergence and cooperation of different signaling cascades are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.365) > PI3K/AKT/mTOR is frequently deregulated in several proliferative disorders, from cancer to overgrowth syndromes and polycystic kidney disease. Despite similar mutations, patients develop a plethora of different disorders. For example, PIK3CA mutations associated with overgrowth syndromes are often similar to those observed in cancer, but these patients do not seem to be predisposed to cancer. Similarly, loss of tumor suppressor genes such as TSC1 and TSC2 is not always accompanied by the development of renal cysts and overgrowth. This suggests that the role of mutations in disease is determined by the context in which they occur. Clinical variability may depend on the timing of the mutation during embryogenesis, the type of tissue affected and concomitant secondary lesions. On the other hand, the common molecular basis of these disorders is associated with significant clinical overlap. This will eventually help to apply the therapeutic strategies used for well-studied pathologies, such as cancer, to emerging clinically relevant diseases, such as overgrowth syndrome and polycystic kidney disease. Conversely, patients with ADPKD did not benefit from rapalogs treatment, indicating that mTOR-mediated signaling is not the only pathway involved in cyst formation. These clinical failures imply that a novel therapeutic option could be based on the single or combined targeting of PI3K pathway components.

[13] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

• Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
• Year: 2025
• Venue: Journal of Veterinary Internal Medicine
• URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
• DOI: 10.1111/jvim.70139
• PMID: 40492724
• PMCID: 12150350
• Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
• Evidence snippets:
• Snippet 1 (score: 0.364) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[14] Macrocephaly and Finger Changes: A Narrative Review

• Authors: C. Lazea, R. Vulturar, A. Chiș, Svetlana Encica, Melinda Horvat et al.
• Year: 2024
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/e961f09225240576c23931aa47acb3df2db1c0a8
• DOI: 10.3390/ijms25105567
• PMID: 38791606
• PMCID: 11122644
• Citations: 1
• Summary: This review aims to provide a current synthetic overview of the main acquired and genetic etiologies associated with macrocephaly and finger changes, to delineate causes of macrocephaly and finger changes, facilitate differential diagnosis and guide for the appropriate etiological framework.
• Evidence snippets:
• Snippet 1 (score: 0.363) > Macrocephaly, characterized by an abnormally large head circumference, often co-occurs with distinctive finger changes, presenting a diagnostic challenge for clinicians. This review aims to provide a current synthetic overview of the main acquired and genetic etiologies associated with macrocephaly and finger changes. The genetic cause encompasses several categories of diseases, including bone marrow expansion disorders, skeletal dysplasias, ciliopathies, inherited metabolic diseases, RASopathies, and overgrowth syndromes. Furthermore, autoimmune and autoinflammatory diseases are also explored for their potential involvement in macrocephaly and finger changes. The intricate genetic mechanisms involved in the formation of cranial bones and extremities are multifaceted. An excess in growth may stem from disruptions in the intricate interplays among the genetic, epigenetic, and hormonal factors that regulate human growth. Understanding the underlying cellular and molecular mechanisms is important for elucidating the developmental pathways and biological processes that contribute to the observed clinical phenotypes. The review provides a practical approach to delineate causes of macrocephaly and finger changes, facilitate differential diagnosis and guide for the appropriate etiological framework. Early recognition contributes to timely intervention and improved outcomes for affected individuals.

[15] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

• Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
• Year: 2025
• Venue: Pathophysiology
• URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
• DOI: 10.3390/pathophysiology32010009
• PMID: 39982365
• PMCID: 12077258
• Citations: 24
• Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
• Evidence snippets:
• Snippet 1 (score: 0.362) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[16] A novel pathogenic variant of DNMT3A associated with craniosynostosis: a case report of Heyn–Sproul–Jackson syndrome

• Authors: G. Kim, Jaewon Kim, Jaewoo Lee, D. Jang
• Year: 2023
• Venue: Frontiers in Pediatrics
• URL: https://www.semanticscholar.org/paper/4593a650bdab490666074d3d6811588ba54430b1
• DOI: 10.3389/fped.2023.1165638
• PMID: 37303757
• PMCID: 10248406
• Citations: 2
• Influential citations: 1
• Summary: A novel feature associated with HESJAS (craniosynostosis) is described, along with a more detailed account of clinical manifestations than those in the original report.
• Evidence snippets:
• Snippet 1 (score: 0.360) > Heyn-Sproul-Jackson syndrome (HESJAS, OMIM #618724) was first described in 2019 by Heyn et al. as a novel cause of microcephalic dwarfism (1). The authors reported three unrelated patients, each aged 13 years, 19 months, and 4.5 years with microcephaly, short stature, low weight, and global developmental delay. HESJAS is caused by heterozygous pathogenic variants in DNMT3A [DNA (cytosine-5)-methyltransferase 3A] on chromosome 2p23. DNMT3A codes for a DNA methyltransferase responsible for DNA methylation patterns in mammals, one of the major epigenetic mechanisms influencing gene expression and cell differentiation (2). Heterozygous variants in the same gene can also cause Tatton-Brown-Rahman syndrome (TBRS, OMIM #615879), a reciprocal phenotype presenting with macrocephaly, overgrowth, and intellectual disability (3). To date, more than 90 individuals with a pathogenic variant in DNMT3A related to TBRS have been reported (4); however, there have been no cases of HESJAS since the initial report. Herein, we describe a patient carrying a novel heterozygous DNMT3A variant, c.1012_1014 + 3del, identified by next generation sequencing, who showed clinical features of HESJAS.

[17] Aortic disease and cardiomyopathy in patients with a novel DNMT3A gene variant causing Tatton-Brown–Rahman syndrome

• Authors: D. Žebrauskienė, E. Sadauskienė, J. Dapkūnas, V. Kairys, Joris Balciunas et al.
• Year: 2024
• Venue: Clinical Epigenetics
• URL: https://www.semanticscholar.org/paper/f76425557fe4051a982a9749b564c511cbffda58
• DOI: 10.1186/s13148-024-01686-y
• PMID: 38845031
• PMCID: 11157947
• Citations: 1
• Summary: From the clinical perspective, it is suggested that new patients diagnosed with congenital DNMT3A variants and TBRS require close examination and follow-up for aortic dilatation and valvular disease because these conditions can progress rapidly.
• Evidence snippets:
• Snippet 1 (score: 0.358) > Tatton-Brown–Rahman syndrome (TBRS) is a rare congenital genetic disorder caused by autosomal dominant pathogenic variants in the DNA methyltransferase DNMT3A gene. Typical TBRS clinical features are overgrowth, intellectual disability, and minor facial anomalies. However, since the syndrome was first described in 2014, a widening spectrum of abnormalities is being described. Cardiovascular abnormalities are less commonly reported but can be a major complication of the syndrome. This article describes a family of three individuals diagnosed with TBRS in adulthood and highlights the variable expression of cardiovascular features. A 34-year-old proband presented with progressive aortic dilatation, mitral valve (MV) regurgitation, left ventricular (LV) dilatation, and ventricular arrhythmias. The affected family members (mother and brother) were diagnosed with MV regurgitation, LV dilatation, and arrhythmias. Exome sequencing and computational protein analysis suggested that the novel familial DNMT3A mutation Ser775Tyr is located in the methyltransferase domain, however, distant from the active site or DNA-binding loops. Nevertheless, this bulky substitution may have a significant effect on DNMT3A protein structure, dynamics, and function. Analysis of peripheral blood cfDNA and transcriptome showed shortened mononucleosome fragments and altered gene expression in a number of genes related to cardiovascular health and of yet undescribed function, including several lncRNAs. This highlights the importance of epigenetic regulation by DNMT3A on cardiovascular system development and function. From the clinical perspective, we suggest that new patients diagnosed with congenital DNMT3A variants and TBRS require close examination and follow-up for aortic dilatation and valvular disease because these conditions can progress rapidly. Moreover, personalized treatments, based on the specific DNMT3A variants and the different pathways of their function loss, can be envisioned in the future.

[18] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

• Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
• Year: 2012
• Venue: Croatian Medical Journal
• URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
• DOI: 10.3325/cmj.2012.53.529
• PMID: 23275318
• PMCID: 3541579
• Citations: 28
• Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
• Evidence snippets:
• Snippet 1 (score: 0.356) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[19] Computational drug discovery approaches identify mebendazole as a candidate treatment for autosomal dominant polycystic kidney disease

• Authors: P. Brownjohn, A. Zoufir, Daniel J O’Donovan, Saatviga Sudhahar, A. Syme et al.
• Year: 2024
• Venue: Frontiers in Pharmacology
• URL: https://www.semanticscholar.org/paper/a595e78572ca02b8cb2897bfc4a989a2b021b279
• DOI: 10.3389/fphar.2024.1397864
• PMID: 38846086
• PMCID: 11154008
• Citations: 3
• Summary: It is determined that the anthelmintic mebendazole was a potent anti-cystic agent in human cellular and in vivo models of ADPKD, and is likely acting through the inhibition of microtubule polymerisation and protein kinase activity.
• Evidence snippets:
• Snippet 1 (score: 0.355) > Targets and molecules were ultimately filtered for validation based on biological and chemical insights, and the potential for clinical translation.Earlier this year, Wilk et al., 2023 applied a similar transcriptomic approach to us, in that case making use of publicly available transcriptomic datasets to create Pkd2-specific ADPKD disease signatures, from which signature reversion was sought from the Library of Integrated Network-based Cellular Signatures (LINCs) drug signature database in order to identify drug repurposing candidates.While one group has previously made use of a knowledge graph-based approach to prioritise preclinically active compounds with the highest chance of clinical translation (Malas et al., 2019), to our knowledge, the current study provides the first combined application of transcriptomic and machine-learning approaches to identify and prioritise putative treatments for ADPKD, and further deconvolute potential mechanisms of action for experimental validation. > In summary we report, using computational, in vitro and in vivo approaches, that the anthelmintic drug mebendazole ameliorates disease-relevant phenotypes in cellular and animal models of ADPKD.We further show that this effect is likely primarily due to the inhibitory effect of mebendazole on the polymerisation of microtubules, which underlie cellular processes important in ADPKD, including cell proliferation, transport, and cilia signalling, and extends previous work linking the importance of the microtubule network to ADPKD pathophysiology.We also describe the inhibitory profile of mebendazole on known and novel protein kinase targets, some of which have previously been implicated in ADPKD, suggesting mebendazole may be acting via polypharmacology to impact disease mechanisms.We acknowledge that further experimental efforts will be required to confirm the actions of mebendazole on these putative targets in relevant disease model systems.It would be particularly informative to investigate these mechanisms in dedicated in vivo studies, where the effects of mebendazole on a wider range of ADPKD-relevant cell types and phenotypes could be evaluated.

Notes

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