結節性硬化症

OBJECTIVE: To explore the molecular mechanism of tuberous sclerosis type 2 caused by TSC2 synonymous mutations affecting normal splicing of precursor mRNA. METHODS: Review and analyses clinical diagnosis and treatment process of a patient with tuberous sclerosis complex type 2, summarize the relationship between genotype and clinical phenotype. Use bioinformatics methods to analyses the effect of TSC2 gene synonymous mutations on precursor mRNA splicing and use in vivo splicing experiments and in vitro minigene experiments to verify the possible pathogenic mechanism of TSC2 gene synonymous mutations. RESULTS: The proband exhibited tuberous sclerosis phenotype including epilepsy and depigmentation. A synonymous mutation in the TSC2 gene (c.1443G > A, p.Glu481=) associated with the phenotype was identified. Bioinformatics analysis suggested that this synonymous mutation may disrupt normal pre-mRNA splicing. Both in vivo splicing assays and minigene experiments confirmed that the synonymous mutation indeed affects proper pre-mRNA splicing. CONCLUSION: TSC2 c.1443G > A (p.Glu481=) synonymous mutation may be associated with tuberous sclerosis type 2 by disrupting normal pre-mRNA splicing.

OBJECTIVE: To describe the spectrum of MRI features, histopathological findings, and clinical outcomes of musculoskeletal PEComas at a single tertiary sarcoma center. MATERIALS AND METHODS: Following institutional ethics approval, orthopedic oncology and pathology databases were searched for histopathologically confirmed musculoskeletal soft tissue PEComas managed between 2000 and 2025. Inclusion required pretreatment MRI. Pulmonary, intra-abdominal/pelvic, and cutaneous lesions were excluded. Demographic and clinical features were reviewed for all cases. MRI examinations were reviewed in consensus by two fellowship-trained musculoskeletal radiologists and archival histopathology by a dedicated musculoskeletal pathologist. RESULTS: Twelve patients met inclusion criteria (7/12 male), mean age 64.3 years (range 16-89 years). One tuberous sclerosis complex (TSC)-associated fibroma-like PEComa appeared as a well-defined periarticular mass with homogeneously low T1 and T2 signal and no significant enhancement. The remaining 11 non-TSC tumors had a mean diameter of 13.0 cm; 10 of 11 were deep to deep fascia, and 6 of 11 showed trans-compartmental extension. Intratumoral nonenhancement consistent with necrosis was present in all 10 contrast-enhanced cases. Neurovascular encasement was identified in 4 of 11 (36%) and osseous invasion in 2 of 11 (18%). All nine histologically evaluable non-TSC cases showed malignant morphology. The overall metastatic rate was 91%, with disease-specific mortality of 64% at a median follow-up of 19 months. CONCLUSION: Musculoskeletal PEComas demonstrate large size, deep location, macroscopic intratumoral necrosis, as well as frequent trans-compartmental extension on MRI. Clinical outcomes reflect aggressive biologic behavior, with high metastatic rates and disease-specific mortality in non-TSC-related PEComas of the musculoskeletal system.

Kidney cystic epithelium primarily comprises proliferating A-intercalated (A-IC) cells in humans and mouse models of TSC. These studies explored the expression of transcription factors (TF) that drive the development of A-IC cells and the downregulation of B-intercalated (B-IC) cells, as well as the status and localization of Tsc1 and Tsc2 in epithelial cells lining the cysts. Transcriptome studies indicated enhanced expression of the following TFs: DMRT2, FOXI1, and FOXP1 in young TSC mice, and DMRT2 and FOXI1 in aged mice. The expression of Hmx2 decreased in TSC mice of all ages. Our studies further demonstrated: (1) distinct and predominant DMRT2 and FOXP1 localization in the cystic epithelium of in TSC mouse models; and (2) expression of Foxi1, Tsc1, and Tsc2 in epithelial cells lining the kidney cysts. Expression of DMRT2, FOXI1, and FOXP1 is enhanced in the A-IC cells lining the kidney cysts of TSC mouse models. In the same models, the expression of Hmx2 mRNA is decreased and is accompanied by the loss of B-IC cells in cyst epithelia. Both DMRT2 and FOXP1 localized to the nucleus of A-IC cells of the renal cysts, suggesting that TSC kidney cystogenesis is driven by factors that exclusively promote A-IC expansion.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) is a rare genetic tumor syndrome characterized by cutaneous fibrofolliculoma and trichodiscomas, lung bullae with an elevated risk of spontaneous pneumothorax and renal cell cancer. OBJECTIVES: Due to rareness of the disease, clinical symptoms and cutaneous manifestations are often misjudged, resulting in delayed medical diagnosis and considerable health risks for patients and their families. Accurate discrimination of fibrofolliculomas from other non-malignant skin tumors can be crucial for early diagnosis and appropriate management of BHDS. In addition, they may clinically overlap with adnexal or follicular papules seen in other rare genodermatoses, including facial angiofibromas in tuberous sclerosis complex, trichilemmomas in Cowden syndrome/PTEN hamartoma tumor syndrome, and trichoepitheliomas in CYLD cutaneous syndrome. METHODS: In this study, skin lesions from 15 BHDS patients with genetic confirmed disease-causing variants in FLCN underwent reflectance confocal microscopy (RCM) and Line-Field Confocal Optical Coherence Tomography (LC-OCT) to systematically analyse the morphologic and microstructural features of fibrofolliculomas. RESULTS: In RCM a dilated follicular unit was seen in 12/15 cases (80%), while in LC-OCT this feature was seen in 13/15 (87%). The characteristic round, onion-like shaped hyperreflective structures with a well-demarcated perifollicular halo, corresponding to the histopathological features of branching chords and strands of epithelial cells was seen in all cases (RCM and LC-OCT 100%), aiding clinicians in identifying fibrofolliculomas. CONCLUSION: Advanced imaging techniques provide a non-invasive approach for early diagnosis of fibrofolliculomas. Therefore, RCM and especially LC-OCT may be promising tools for enhancing the diagnostic precision and sufficient clinical management of Birt-Hogg-Dubé syndrome.

Activation of the mechanistic target of rapamycin (mTOR) complex1 (mTORC1) promotes muscle protein synthesis, mass, and function. Muscle mTORC1 can be activated by feeding and contraction. Here, muscle mTORC1 signaling, protein synthesis, mass, and function are characterized in a genetic mouse model that separates these two major modes of muscle mTORC1 regulation. AKT signaling is required for feeding-induced muscle mTORC1 signaling and protein synthesis, and mice expressing a mutant of tuberous sclerosis complex 2 (TSC2) that cannot be phosphorylated by AKT specifically in skeletal muscle (SkM-TSC2-5A) attenuate these effects of feeding. Despite this loss of postprandial protein synthesis, SkM-TSC2-5A mice have similar muscle and myofiber size compared to SkM-TSC2-WT mice. SkM-TSC2-5A mice maintain normal muscle mTORC1 activation in response to contraction and exhibit no differences in atrophy-related gene expression or ribosomal content. SkM-TSC2-5A mice exhibit improved maximal endurance capacity without changes in muscle contractile function. This phenotype occurs without alterations in muscle glycogen content or myofiber type but does coincide with a modest increase in muscle mitochondrial content. Therefore, AKT-mediated phosphorylation of TSC2 is required for postprandial mTORC1 activation and the induction of protein synthesis; however, these are dispensable for the development and maintenance of muscle mass in sedentary mice.