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Biomaterials Oct 2022Cell reprogramming can satisfy the demands of obtaining specific cell types for applications such as tissue regeneration and disease modeling. Here we report the...
Cell reprogramming can satisfy the demands of obtaining specific cell types for applications such as tissue regeneration and disease modeling. Here we report the reprogramming of human fibroblasts to produce chemically-induced osteogenic cells (ciOG), and explore the potential uses of ciOG in bone repair and disease treatment. A chemical cocktail of RepSox, forskolin, and phenamil was used for osteogenic induction of fibroblasts by activation of RUNX2 expression. Following a maturation, the cells differentiated toward an osteoblast phenotype that produced mineralized nodules. Bulk and single-cell RNA sequencing identified a distinct ciOG population. ciOG formed mineralized tissue in an ectopic site of immunodeficiency mice, unlike the original fibroblasts. Osteogenic reprogramming was modulated under engineered culture substrates. When generated on a nanofiber substrate ciOG accelerated bone matrix formation in a calvarial defect, indicating that the engineered biomaterial promotes the osteogenic capacity of ciOG in vivo. Furthermore, the ciOG platform recapitulated the genetic bone diseases Proteus syndrome and osteogenesis imperfecta, allowing candidate drug testing. The reprogramming of human fibroblasts into osteogenic cells with a chemical cocktail thus provides a source of specialized cells for use in bone tissue engineering and disease modeling.
Topics: Animals; Biocompatible Materials; Bone Regeneration; Cell Differentiation; Cells, Cultured; Colforsin; Core Binding Factor Alpha 1 Subunit; Humans; Mice; Osteoblasts; Osteogenesis; Tissue Engineering
PubMed: 36116170
DOI: 10.1016/j.biomaterials.2022.121792 -
European Journal of Ophthalmology Sep 2023In this report we illustrate the ophthalmologic assessment of two patients affected by Proteus Syndrome (PS), an extremely rare genetic disorder. Case #1 describes a 26...
In this report we illustrate the ophthalmologic assessment of two patients affected by Proteus Syndrome (PS), an extremely rare genetic disorder. Case #1 describes a 26 year old male patient followed for multiple ophthalmic anomalies: a limbal dermoid cyst, a unilateral cataract, bilateral nystagmus, severe myopia and unilateral optic nerve head drusen. Case #2 describes a 20 year old female patient referred to our Ophthalmology Department for a routine ophthalmologic evaluation after being treated for 3 years with Miransertib (an experimental AKT-pathway inhibitor). Both patients underwent a complete ophthalmologic examination and a multimodal imaging evaluation. The multimodal imaging approach has revealed useful to evaluate both cases in detail and to keep track of disease evolution over time, moreover providing helpful features to further characterize this rare syndrome.
Topics: Male; Female; Humans; Young Adult; Adult; Proteus Syndrome; Eye Abnormalities; Nystagmus, Pathologic; Diagnostic Imaging; Myopia; Abnormalities, Multiple
PubMed: 36113118
DOI: 10.1177/11206721221125852 -
The Turkish Journal of Pediatrics 2022PTEN hamartoma tumor syndrome (PHTS) is an umbrella term including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS),...
BACKGROUND
PTEN hamartoma tumor syndrome (PHTS) is an umbrella term including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and PTEN-related Proteus-like syndrome. One of the disorders in PHTS spectrum, CS is characterized by macrocephaly, mucocutaneous findings, gastrointestinal system (GIS) polyposis and an increased lifetime risk of GIS, breast, thyroid and other cancers.
CASE
In this study, we report an adolescent patient presenting with recurrent life-threatening upper GIS bleeding as a result of hamartomatous polyposis. Genetic studies revealed a known pathogenic nonsense mutation confirming the initial diagnosis of CS.
CONCLUSIONS
Additionally, we describe our therapeutic intervention to improve the patient`s clinical symptoms with sirolimus, which its use is infrequently addressed in the literature for pediatric age group harboring PTEN mutations.
Topics: Adolescent; Child; Hamartoma Syndrome, Multiple; Humans; Melena; PTEN Phosphohydrolase; Sirolimus; Thyroid Gland
PubMed: 36082652
DOI: 10.24953/turkjped.2021.5330 -
The Journal of Investigative Dermatology Sep 2022Mosaicism results from postzygotic alterations during embryogenesis leading to genetically distinct populations of cells within individuals and has been historically...
Mosaicism results from postzygotic alterations during embryogenesis leading to genetically distinct populations of cells within individuals and has been historically recognized by phenotypes with visible, often patterned manifestations. Before the advent of molecular profiling assays and high-throughput sequencing, it was challenging to study mosaicism in human disease; however, the study of mosaic disorders has recently revealed unexpected and novel pathways for disease pathogenesis. In this paper, we will review the techniques for discovery of disease-causing alleles using Proteus syndrome; phakomatosis pigmentokeratotica; linear porokeratosis; and vacuoles, E1 enzyme, X-linked, autoinflammatory somatic syndrome as models. These tools represent powerful approaches for dissecting the genetic basis for human disorders.
Topics: Alleles; High-Throughput Nucleotide Sequencing; Humans; Mosaicism; Nevus, Pigmented; Proteus Syndrome; Skin Diseases, Genetic
PubMed: 35985765
DOI: 10.1016/j.jid.2022.07.001 -
Annals of the American Thoracic Society Nov 2022Limited information is available regarding cystic lung disease in syndrome, a rare overgrowth disorder caused by a somatic activating variant in . To define the...
Limited information is available regarding cystic lung disease in syndrome, a rare overgrowth disorder caused by a somatic activating variant in . To define the phenotype of cystic lung disease in syndrome. Medical records, pulmonary function tests, and chest computed tomography of 39 individuals with syndrome evaluated at a single center were retrospectively reviewed. Lung histopathology from five affected individuals was examined. Cystic lung disease affected 26 (67%) of 39 individuals. The mean age of affected individuals was 17.1 years. The lung cysts varied in size and location. Focal regions of heterogeneous lung parenchyma resembling emphysema were found in 81% of affected individuals. Mass effect was seen in 12% of affected individuals; pneumothorax occurred in one. Dyspnea and respiratory infections were reported by 38% and 35% of affected individuals, respectively. Abnormal pulmonary function and scoliosis were found in 96% of affected individuals. Lung disease progressed in seven of 10 affected individuals, and all five affected individuals younger than 20 years of age had progressive cystic lung disease. Three affected individuals had symptomatic improvement after lung resection. Histopathology showed cystic air space enlargement of varying severity. Cystic lung disease is common in syndrome and is likely to progress in affected individuals younger than 20 years of age. Screening asymptomatic individuals with syndrome for cystic lung disease is indicated. Surgical lung resection is a therapeutic option for affected individuals with severe disease. Clinical trial registered with www.clinicaltrials.gov (NCT00001403).
Topics: Humans; Proteus Syndrome; Retrospective Studies; Lung Diseases; Phenotype; Pulmonary Emphysema; Cysts
PubMed: 35839129
DOI: 10.1513/AnnalsATS.202111-1214OC -
Postmortem Diagnosis of the Proteus Syndrome by Next Generation Sequencing of Affected Brain Tissue.Academic Forensic Pathology Jun 2022We report a case of a somatic overgrowth syndrome diagnosed at forensic autopsy with the aid of next generation sequencing as Proteus syndrome. Somatic overgrowth...
We report a case of a somatic overgrowth syndrome diagnosed at forensic autopsy with the aid of next generation sequencing as Proteus syndrome. Somatic overgrowth syndromes result from spontaneous somatic mutations that arise early in development and display a mosaic pattern of expression in patient tissues. Due to the temporal and anatomic heterogeneity of these syndromes, phenotypes vary widely, resulting in clinical overlap. Furthermore, the variable ratio of mutated to nonmutated cells in patient tissue can result in low-level mutations that could be missed using Sanger sequencing. Due to these factors, recent literature points to next generation sequencing (NGS) as an adjunct to diagnosis of these rare entities. A male in his fourth decade of life presented to our forensic autopsy service with physical features suggestive of a somatic overgrowth syndrome. Due to the paucity of clinical information accompanying the individual, a definitive diagnosis based on physical characteristics, alone, was not possible. Next generation sequencing of affected formalin-fixed and paraffin-embedded brain tissue confirmed the presence of the variant in (c.49G>A, p.Glu17Lys, in 14.13% of reads) found in Proteus syndrome. To our knowledge, this is the first report of the mosaic variant of detected in brain tissue and the first reported case of a postmortem diagnosis of Proteus syndrome with the aid of NGS. We conclude that NGS can be used as an adjunctive method to support a specific diagnosis among the somatic overgrowth syndromes postmortem in the absence of sufficient clinical history.
PubMed: 35799996
DOI: 10.1177/19253621221097294 -
Pulmonary Circulation Apr 2022Proteus syndrome is a rare progressive multisystem disorder characterized by asymmetric, disproportionate overgrowth of bone, skin, and other tissue types. Molecular...
Proteus syndrome is a rare progressive multisystem disorder characterized by asymmetric, disproportionate overgrowth of bone, skin, and other tissue types. Molecular pathogenesis has been identified as somatic activating mutations of the AKT1 gene. The presentation of Proteus syndrome is exceptionally variable. Respiratory complications include emphysematous lung disease and predisposition to pulmonary emboli, the latter of which is a significant source of mortality. Pulmonary hypertension due to longstanding hypoxic lung disease as well as chronic thromboembolic events has been observed in this population. In contrast, precapillary pulmonary arterial hypertension in the absence of chronic pulmonary emboli and parenchymal lung disease has not been described in the literature on patients with Proteus syndrome. We report such a case in a young patient with Proteus syndrome, reviewing subsequent management and emphasizing the need for a detailed investigation of dyspnea.
PubMed: 35783033
DOI: 10.1002/pul2.12098 -
Children (Basel, Switzerland) Jun 2022. Infantile hemangiomas may have unexpected behavior. Initial regression (spontaneously or drug-induced) may be followed by unexplained recurrences. At this moment,...
. Infantile hemangiomas may have unexpected behavior. Initial regression (spontaneously or drug-induced) may be followed by unexplained recurrences. At this moment, there are no well-established criteria to predict infantile hemangioma reccurrences. . We compared the VEGF pathway gene expression profile for one case of involuting infantile hemangioma versus one case of recurrent proliferative infantile hemangioma using TaqMan Array. . We found ten genes upregulated for both involuting and recurrent proliferative hemangiomas: ACTB, KRAS, MAP2K1, HRAS, NOS3, BAD, HSPB1, HPRT1, GUSB, and CASP9. Thirteen genes were downregulated for both involuting and proliferative hemangiomas: FIGF, ACTG1, GRB2, MAPKAPK2, ACTG2, MAP2K2, MAPK3, HSP90AA1, MAP2K6, NRAS, ACTA1, KDR, and MAPK1. Three genes showed divergent expression between proliferating and involuting hemangiomas. Proliferating hemangioma had MAPK14 and AKT1 gene upregulation and ACTA2 downregulation. Involuting infantile hemangioma was characterized by ACTA2 upregulation and AKT1 and MAPK14 downregulation. . Three genes, AKT1, p38/MAPK14, and ACTA2, were found to have divergent expression in proliferating and involuting infantile hemangiomas. Excepting AKT1, which was mentioned in the last ISSVA classification (strictly related to Proteus Syndrome), none of the other genes were reported. An accurate gene expression profile mapping of infantile hemangiomas together with a gene expression-based hemangioma classification is stringently needed.
PubMed: 35740845
DOI: 10.3390/children9060908 -
Clinical Genetics Sep 2022Proteus syndrome is a very rare disorder with progressive, asymmetrical, and disproportionate overgrowth of body parts with a highly variable phenotype. It is associated...
Proteus syndrome is a very rare disorder with progressive, asymmetrical, and disproportionate overgrowth of body parts with a highly variable phenotype. It is associated with mosaicism for the recurrent heterozygous somatic gain-of-function variant c.49G>A (p.Glu17Lys) in the protein kinase AKT1. We report on a girl with a progressive intraosseous lipoma of the frontal bone and additional, nonspecific features including mild developmental delay, strabism, and a limbal dermoid of the left eye. She did not fulfill the criteria for a clinical diagnosis of Proteus syndrome. However, mutation analysis of AKT1 in a lipoma biopsy revealed this specific activating variant. Several cases of progressive intraosseous lipoma of the frontal bone have been reported in the literature. Only in two of these observations, a tentative diagnosis of Proteus syndrome was made, based on additional clinical features, although without molecular-genetic verification. We conclude that oligosymptomatic Proteus syndrome should be considered in progressive intraosseous lipoma, as recognition of this diagnosis has relevant implications for genetic counseling and opens novel treatment options with AKT1 inhibitors rather than surgical procedures.
Topics: Female; Humans; Lipoma; Mosaicism; Proteus Syndrome; Proto-Oncogene Proteins c-akt
PubMed: 35670639
DOI: 10.1111/cge.14174 -
Cureus May 2022Proteus syndrome (PS) is a rare overgrowth disease process with only a few hundred cases being reported in the literature. Abnormal formation of the vertebral bodies...
Proteus syndrome (PS) is a rare overgrowth disease process with only a few hundred cases being reported in the literature. Abnormal formation of the vertebral bodies causing scoliosis and spinal stenosis are common features that lead to debilitating pain in these patients. We present a case of a 35-year-old male landscaper with a history of PS causing severe scoliosis and vertebral overgrowth who underwent recurrent sets of multilevel zygapophyseal joint injections for management of his axial back pain. This case illustrates the utility of interventional spinal procedures in patients with progressive pain from PS.
PubMed: 35663702
DOI: 10.7759/cureus.24651