A second hit somatic (p.R905W) and a novel germline intron-mutation of TSC2 gene is found in intestinal lymphangioleiomyomatosis: a case report with literature review

Han, Bogyeong; Lee, Juhwan; Kwak, Yoonjin; Kim, Ho; Lee, Kwang Hoon; Shim, Yumi; Lee, Hyunju; Park, Jong Bae

doi:10.1186/s13000-021-01138-8

Cited by 3 publications

(2 citation statements)

References 46 publications

(53 reference statements)

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“…The two-hit model has also been reported in two TSC patients with HME, where a germline variant in TSC1/TSC2 was found in blood and a second somatic variant in the same gene was found in brain-derived samples [ 107 ]. Similar findings have also been reported for facial angiofibromas, where half of individuals with TSC1/TSC2 pathogenic variants also presented with a second hit in the affected tissue as well as renal AMLs and LAM [ 116 , 120 , 121 ].…”

Section: Updates To Genotype–phenotype Correlations In Tsc: Mosaicism...supporting

confidence: 82%

“…Over the years, different tissue samples have also been used for the detection of mosaic variants in patients affected by mTORopathies. Overall, greater success has been achieved detecting mosaic variants in affected samples, such as resected brain, LAM, angiofibroma, or AML tissue [ 11 , 105 , 116 , 120 ]. Patients do not always receive surgical intervention, and even if they do, it is useful to identify pathogenic variants prior to surgery.…”

Section: Advances In Detection Of Pathogenic Variants In Tsc and Mtor...mentioning

confidence: 99%

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The Genetics of Tuberous Sclerosis Complex and Related mTORopathies: Current Understanding and Future Directions

Man,

Di Scipio,

Grewal

et al. 2024

Genes

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The mechanistic target of rapamycin (mTOR) pathway serves as a master regulator of cell growth, proliferation, and survival. Upregulation of the mTOR pathway has been shown to cause malformations of cortical development, medically refractory epilepsies, and neurodevelopmental disorders, collectively described as mTORopathies. Tuberous sclerosis complex (TSC) serves as the prototypical mTORopathy. Characterized by the development of benign tumors in multiple organs, pathogenic variants in TSC1 or TSC2 disrupt the TSC protein complex, a negative regulator of the mTOR pathway. Variants in critical domains of the TSC complex, especially in the catalytic TSC2 subunit, correlate with increased disease severity. Variants in less crucial exons and non-coding regions, as well as those undetectable with conventional testing, may lead to milder phenotypes. Despite the assumption of complete penetrance, expressivity varies within families, and certain variants delay disease onset with milder neurological effects. Understanding these genotype–phenotype correlations is crucial for effective clinical management. Notably, 15% of patients have no mutation identified by conventional genetic testing, with the majority of cases postulated to be caused by somatic TSC1/TSC2 variants which present complex diagnostic challenges. Advancements in genetic testing, prenatal screening, and precision medicine hold promise for changing the diagnostic and treatment paradigm for TSC and related mTORopathies. Herein, we explore the genetic and molecular mechanisms of TSC and other mTORopathies, emphasizing contemporary genetic methods in understanding and diagnosing the condition.

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Section: Updates To Genotype–phenotype Correlations In Tsc: Mosaicism...supporting

confidence: 82%

Section: Advances In Detection Of Pathogenic Variants In Tsc and Mtor...mentioning

confidence: 99%

The Genetics of Tuberous Sclerosis Complex and Related mTORopathies: Current Understanding and Future Directions

Man,

Di Scipio,

Grewal

et al. 2024

Genes

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Brain parenchymal angiomatoid fibrous histiocytoma and spinal myxoid mesenchymal tumor with FET: CREB fusion, a spectrum of the same tumor type

Kim

Park

et al. 2022

Neuropathology

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Angiomatoid fibrous histiocytomas (AFH) is a rare soft tissue tumor of intermediate malignant potential, and its histology is diverse. It can occur in several organs including intracranial and soft tissues. Here, we report two cases of brain parenchymal classic AFH and spinal extramedullary myxoid mesenchymal tumor with clinicopathological and molecular investigations by next‐generation sequencing and a comprehensive review. The current brain parenchymal AFH occurred in a 79‐year‐old woman, and the spinal myxoid mesenchymal tumor arose in the thoracic spine of a 28‐year‐old woman; both harbored FET:CREB fusion. The current brain parenchymal AFH has not recurred for 15‐months follow‐up period, but the spinal myxoid mesenchymal tumor recurred three times and metastasized to T8 spine level for 30‐months follow‐up period. We reviewed 40 reported cases of central nervous system (CNS) AFHs/myxoid mesenchymal tumors including our two cases to identify clinicopathological features and biological behaviors. They occur with a slight female predominance (M:F = 1:1.7) in children and young adults (median age: 17 years; range: 4–79 years old). Approximately 80% of CNS AFHs were younger than 30 year. Most of them were dura‐based and were not just intracranial tumors as they occurred anywhere in the CNS including spinal dura. EWSR1 rearrangement was the most common driver (98%), including FET:CREB (33%), EWSR1:ATF1 (30%), and EWSR1:CREM (27%) fusions, but FUS:CREM fusion (2%) was also present. During the follow‐up period (median: 27 months), 43% (17/40) of CNS AFHs recurred between two months and 11 years, and multiple recurrences were also observed. One case showed metastases to the lymph nodes and vertebrae, and among 11 cases that resulted in death, four cases provided available clinical data. Because these tumors are identical to soft tissue AFH or primary pulmonary myxoid sarcoma with an FET:CREB fusion in morphological and immunohistochemical spectra, the authors propose incorporating the two tumor terms into one.

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The Epidemiology and Clinical Features of Lymphangioleiomyomatosis (LAM): A Descriptive Study of 33 Case Reports

Shah,

Patel,

Shah

et al. 2023

Cureus

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Lymphangioleiomyomatosis (LAM) is a rare, slow-growing metastasizing neoplasm in which smooth muscle-like cells infiltrate the lung parenchyma and cause cystic lung damage. The common early symptoms include shortness of breath, pneumothorax, and chest pain. Lymphangioleiomyomatosis mainly involves the lungs, kidneys, and lymph nodes. This study reviews the characteristics of lymphangioleiomyomatosis to identify any possible changes in the prevalence of symptoms of the disease. We conducted a literature review of case reports on lymphangioleiomyomatosis from PubMed and Google Scholar. Variables of interest were age, gender, symptoms, vitals, immunostaining, and radiological findings. Data were transferred to an Excel spreadsheet (Microsoft Corporation, Redmond, WA), and mean, median, standard deviation, frequencies, and proportions were calculated using R version 1.1.456 (RStudio: Integrated Development for R. RStudio, PBC, Boston, MA). Lymphangioleiomyomatosis is a rare case and so not much of the literature could be found online. Thirty-three case reports were included in this study, and females accounted for 78.78% of the presentations. The average age was 38 years, SD 14.41 years. Shortness of breath was the most frequent symptom (60.6%), followed by pneumothorax (57.57%), chest pain (42.42%), cough (24.24%), and pleural effusion (1.25%).

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A second hit somatic (p.R905W) and a novel germline intron-mutation of TSC2 gene is found in intestinal lymphangioleiomyomatosis: a case report with literature review

Cited by 3 publications

References 46 publications

The Genetics of Tuberous Sclerosis Complex and Related mTORopathies: Current Understanding and Future Directions

The Genetics of Tuberous Sclerosis Complex and Related mTORopathies: Current Understanding and Future Directions

Brain parenchymal angiomatoid fibrous histiocytoma and spinal myxoid mesenchymal tumor with FET: CREB fusion, a spectrum of the same tumor type

The Epidemiology and Clinical Features of Lymphangioleiomyomatosis (LAM): A Descriptive Study of 33 Case Reports

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