Formation Of Hamartomas Research Articles

Commentary: mTOR inhibition suppresses established epilepsy in a mouse model of cortical dysplasia.

Commentary: mTOR inhibition suppresses established epilepsy in a mouse model of cortical dysplasia.

A case report of hepatocellular carcinoma and concurrent pancreatic neuroendocrine tumor and renal angiomyolipoma in a patient with tuberous sclerosis

Tuberous sclerosis complex (TSC) is an inherited, neurocutaneous disorder that presents with the formation of hamartomas involving multiple organ systems. Most commonly affected sites include the kidney, heart, and brain. Pancreatic and hepatic lesions are less commonly reported, and there are currently no definitive screening guidelines for abdominal neoplasms in tuberous sclerosis patients. In this case report, we present a patient with TSC who developed pancreatic neuroendocrine tumor, renal angiomyolipoma, and hepatocellular carcinoma.

Familial Tuberous Sclerosis: a case report

<p class="abstract"><span lang="EN-US">Tuberous sclerosis is a neurocutaneous syndrome with an autosomal dominant inheritance. Tuberous sclerosis complex Syndrome caused by mutations of either the TSC1 orTSC2 gene encoding hamartin and tuberin respectively. It is characterized by the development of benign tumors; the most common oral manifestations of TSC are fibromas (angiofibromas), gingival hyperplasia and enamel hypoplasia and the formation of hamartomas in multiple organ systems leading to morbidity and mortality. Familial tuberous sclerosis probably occurs more often than is indicated by the literature: many family members show signs of being carriers of gene for the disease when carefully examined. We report a case of 25 year old female with the features of Tuberous sclerosis complex like seizures, papules over the cheek, shagreen patch, hypomelanotic macule on arm, buttacks, pulmonary lymphangioleiomyomatosis, subependymal nodules and tubers in brain, angiomyolipoma in both kidneys and Cardiac rhabdomyoma. This article reports on a family with documented tuberous sclerosis in three generations.</span></p>

Tuberous sclerosis complex: Angiofibroma vipula/proliferanza?

Tuberous sclerosis complex (TSC) represents a genetic disorder of hamartoma formation in many organs; particularly the skin, brain, eye, kidney, and heart. We are reporting a case of TSC in a patient and his daughter. The interesting feature is the appearance of the facial angiofibromas in this patient. In this patient, there was a sudden spurt in growth of these lesions in the last 7 months at the age of 50 years giving an appearance of nodular growth, misleading the diagnosis. The lesion was biopsied to know any secondary changes had occurred. There is no mention in the literature regarding such a rapid growth or any secondary changes occurring in angiofibromas. Neither the biopsy revealed any secondary changes. Hence, this interesting phenomenon has been reported. Is it apt to call it as “ANGIOFIBROMA PROLIFERANZA” or “ANGIOFIBROMA VIPULA”? (The word VIPULA in local South Indian Kannada language is prolific growth).

Analysis of twenty pediatric cases of tuberous sclerosis complex: are we doing enough?

Tuberous sclerosis complex (TSC) is a neuro-cutaneous disease characterized by hamartoma formation in various organs particularly the skin, brain, eye, kidney, heart and lungs. Patients usually have multisystem involvement and thus present to different medical specialties with varied complaints while the true nature of the disease and the hidden manifestations may remain unattended. To assess the frequency and characteristics of various cutaneous and systemic manifestations in TSC and the total impact on different system in a cohort of pediatric patients. The study included 20 patients fulfilling the diagnostic criteria for TSC from dermatology, pediatrics, and neurology department. Detailed history, examination, and investigations such as chest X-ray, electrocardiography (ECG), ultrasonography (USG) abdomen, echocardiography, fundoscopy, computed tomography (CT) scan of brain and abdomen were done. Dermatological manifestations included ash leaf macules, angiofibromas, shagreen patch, and fibrous plaque. Systemic findings observed were subependymal calcified nodules, subependymal giant cell astrocytoma, cortical tubers, renal cysts, angiomyolipomas, lung cyst, retinal hamartomas, mental deficits and epilepsy. Wechsler's Intelligence Scale for Children would have been more appropriate for assessing the intelligence. Dental check-up was not done in our group of patients. Our study highlights the wide variety of cutaneous and systemic manifestations of TSC. The study emphasizes the need for comprehensive multidisciplinary treatment and periodic follow-up which are necessary for appropriate management of this multisystem disorder. Counseling regarding education and rehabilitation of the patients and genetic counseling of parents are important.

PTEN Hamartoma Tumour Syndrome:Gastrointestinal Manifestations ofTwo Cases Diagnosed in Singapore

PTEN hamartoma tumour syndrome is associated with germline mutations in the tumour suppressor gene, PTEN (phosphatase and tensin homolog gene), leading to formation of hamartomas due to unregulated cellular proliferation. Two patients presented with complications of hamartomas, which subsequently revealed multiple polyposis of mixed histologies throughout their gastrointestinal tracts. There was no family history for PTEN hamartoma tumour syndrome and both were eventually detected to have de novo PTEN mutations. Despite fulfilling diagnostic criteria and having high probabilities of a PTEN mutation (computed using PTEN Cleveland Clinic score), there was delayed diagnosis of PTEN hamartoma tumour syndrome due to limited awareness amongst treating clinicians. Thus PTEN hamartoma tumour syndrome should still be considered as a differential in patients with similar gastrointestinal manifestations for early diagnosis and intervention.

Using Sirolimus for Posttransplant Management and Reduction of Tuberous Sclerosis Complex Progression in a Patient with End Stage Renal Disease Caused by Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is a neurocutaneous disease characterized by the formation of hamartomas in multiple organs. TSC can show lesions including facial angiofibroma, shagreen patch on the skin, cortical tuber, subependymal nodule, astrocytoma in the brain, cardiac rhabdomyoma, and renal angiomyolipoma. In particular, renal angiomyolipoma may be a cause of end-stage renal disease (ESRD). On the other hand, sirolimus has regulatory effects on cellular growth and proliferation via its inhibitory effect on a protein, mammalian target of rapamycin. We report on a case of an 18-year-old male who underwent renal transplantation due to ESRD induced by TSC. Sirolimus played a role in successful treatment of TSC and effective immunosuppression for transplantation.

Annual review of children with tuberous sclerosis

Tuberous sclerosis complex is a complex childhood disorder characterised by the formation of hamartomas in multiple organs. Annual review of this disease is recommended to monitor the development of complications....

Esclerose Tuberosa – Relato de Caso

Objective. Report a case of Tuberous Sclerosis on childhood. Meth­od. Database research and comparison with the case report. Results. Tuberous Sclerosis (TS) is an autosomal dominant disease that leads to the formation of hamartomas in multiple organs. From 80 to 90% of individuals affected by TS present seizures during the disease, and seizures are the first clinical sign in 90% of the cases. This female patient, aged 2 years 1 month, presented hypopigmented macules on right abdomen, right infrapatellar, left inguinal and left infraoc­cipital areas, as well as little erythematous nodules on the cheek and nose. Presented the first seizure at 4 years-old, associated to impaired neuropsychomotor development. Imaging exams demonstrated sub­ependimal nodules, suggesting a diagnosis of TS on childhood. The patient is being treated with phenytoin for seizures, obtaining control of the symptoms. Conclusions. The patient presented the two most common characteristics of TS – hypopigmented macules and seizures. The treatment for the macules is surgical resection. The Phenytoin, in opposition to the literature, succeeded in control of seizures. Genetic counseling is suggested due to the autosomal dominant expression and to the fact of 85% of the cases resulting in abortion.

Nursing Implications for the Lifelong Management of Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is a genetic disorder that can affect multiple organ systems, including the brain, heart, skin, kidney, and lung, by formation of benign hamartomas. It can be associated with autism, epilepsy, and other neurocognitive and behavioral disabilities. The incidence of TSC is approximately 1 in 6,000 live births, but it may be underdiagnosed. Mutations to either the TSC1 (coding for hamartin) or TSC2 (coding for tuberin) genes are present in 85% of patients with TSC. The TSC1/TSC2 protein dimer complex is a crucial inhibitory element in the mammalian target of rapamycin (mTOR) complex 1 pathway that regulates cell growth and proliferation. The manifestations of TSC usually require management over the entire life of the patient. Until recently, there were few options, other than surgical removal, for treating the symptoms of TSC related to growth of hamartomas. Increased understanding of the genetic cause of the disease and the underlying dysregulation of the mTOR pathway has led to clinical trials of mTOR inhibitors including sirolimus and everolimus. This article will review the various manifestations of TSC and describe treatment strategies, recommendations for surveillance, and use of mTOR inhibitors in their management.

Rapamycin has a beneficial effect on controlling epilepsy in children with tuberous sclerosis complex: results of 7 children from a cohort of 86

Tuberous sclerosis complex (TSC) is a genetic disorder characterized by the formation of hamartomas in various organ systems. We would like share our experience from 86 patients and the results of rapamycin treatment in seven children with TSC. Eighty-six children with TSC were enrolled into this retrospective study. The clinical features of seven children treated with oral rapamycin were presented in detail. The most common complaint of administration was convulsion in 77 children (89.5%). Hypopigmented skin lesions, adenoma sebaceum, resistant epilepsy, intracardiac mass, renal angiomyolipomas, and West syndrome were detected (n = 83, 96.5%; n = 47, 54.7%; n = 36, 41.9%; n = 27, 31.4%; n = 18, 20.9%; and n = 13, 15.1%, respectively). Subependymal nodules were the most frequent finding in cranial imaging followed by cortical tubers and subependymal giant cell astrocytomas (n = 75, 87.2%; n = 71, 82.6%; and n = 8, 9.3%, respectively). Of the seven patients treated with rapamycin, the lesions of six children with facial adenoma sebaceum showed regression in various degrees. The frequency of convulsions decreased in five patients with resistant epilepsy within the first 6 months of the treatment, and complete control of convulsion for all patients was achieved in the second 6 months. This is the first study that showed that rapamycin is an effective agent for controlling epilepsy without any significant side effect in children with TSC. Rapamycin seems to be effective after 6 months of therapy, and we recommend tapering the dosage after successful management of epilepsy.

Abstract 1576: Mesenchymal disruption of Tsc2 in mice results in highly vascular hamartomas.

Abstract Patients with tuberous sclerosis complex (TSC) suffer from the formation of multi-organbenign tumors. Skin tumors from TSC patients are characterized by increased vascularity, fibrosis, and overactivation of mTORC1 signaling due to inactivation of either of the tumor suppressor genes TSC1 or TSC2 in fibroblasts. The role of the TSC2 gene in cells of mesenchymal origin with respect to tumor formation still remains unclear. To investigate the roles of TSC2 in these cells, we used the cre/loxP system to conditionally disrupt mouse Tsc2 in tissues derived from mesenchymal cells. Mice with floxed Tsc2 alleles were mated with mice expressing the cre recombinase transgene under the control of a Prrx1 regulatory element (Prrx1-cre), which is selectively expressed in craniofacial and limb bud mesenchyme. Cells with homozygous Tsc2 floxed alleles expressing the Prrx1-cre transgene (termed here “Tsc2cKO mice”) efficiently eliminated Tsc2 expression from fibroblasts isolated from limb and ventral skin. An EYFP reporter transgene was also present to track cells expressing cre recombinase. Fibroblasts grown from the skin of Tsc2cKO mice expressed EYFP, lacked Tsc2 protein and had elevated levels of phosphorylated ribosomal protein S6, a marker of mTORC1 signaling. Tsc2cKO mice had shortened lifespan with a median survival between 5 and 6 months of age. Tumors were observed in spleen and forepaws of nearly all mice, and tumors involving the liver, skin, skeletal muscle, mediastinum, and kidney also occurred. These results were unexpected due to the lineage restriction of the Prrx1-cre transgene. Tumor formation began to appear on forepaws near the heel of the paw pad as early as 3 weeks of age. By 6 weeks of age the lesions generally showed a reddish appearance. In mice serially imaged by MRI, splenic tumors were apparent by 10-12 weeks of age and renal tumors were apparent by 7-8 weeks. Histologically, the forepaw, splenic, and hepatic tumors were benign fibrovascular proliferations with perivascular cells that stained with smooth muscle actin, most prominently in the spleen. Using ex vivo fluorescent imaging, EYFP fluorescence was not detected in internal organs of control mice containing Prrx1-cre, but strong fluorescence was observed in the splenic, hepatic, and renal tumors of Tsc2cKO mice. In summary, we have developed model system to study the role of Tsc2-deficient mesenchymal cells in hamartoma formation. Citation Format: Peter Klover, Rajesh Thangapazham, Shaowei Li, Jiro Kato, Stasia A. Anderson, Victoria Hoffman, Ji-an Wang, Joshua Bernstock, Elizabeth McCart, Joel Moss, Thomas Darling. Mesenchymal disruption of Tsc2 in mice results in highly vascular hamartomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1576. doi:10.1158/1538-7445.AM2013-1576

Emerging Treatments in the Management of Tuberous Sclerosis Complex

Tuberous sclerosis complex is a genetic disorder characterized by the formation of nonmalignant hamartomas in the brain, heart, skin, kidney, lung, and other organs. It is associated with autism, epilepsy, and other neurocognitive and behavioral disabilities. Wide phenotypic variation occurs in disease severity and natural course: some patients demonstrate minimal effects, e.g., skin changes; others manifest profound seizures and mental retardation. Tuberous sclerosis complex is caused by mutations in either the tuberous sclerosis complex 1 or 2 gene (coding for hamartin and tuberin, respectively). The tuberous sclerosis complex 1/tuberous sclerosis complex 2 protein dimer complex is a crucial inhibitory element in the mammalian target of rapamycin pathway, regulating cell growth and proliferation. Until recently, few options existed, other than surgery, for treating symptoms of tuberous sclerosis complex related to the growth of hamartomas. Increased understanding of the genetic cause of the disease and underlying dysregulation of the mammalian target of rapamycin pathway has led to clinical trials of mammalian target of rapamycin inhibitors, including sirolimus and everolimus. This review gives an overview of tuberous sclerosis complex and its molecular causes, and summarizes results from recent clinical trials of mammalian target of rapamycin inhibitors in patients with the disease.

Bone Morphogenetic Protein-2 and -4 Play Tumor Suppressive Roles in Human Diffuse-Type Gastric Carcinoma

A relationship exists between defects in bone morphogenetic protein (BMP) signaling and formation of hamartoma and adenoma in the gastric epithelium; however, the role of BMP signaling in the progression of diffuse-type gastric carcinoma remains unknown. We investigated whether BMP functions as a tumor suppressor in human diffuse-type gastric carcinoma using three different human diffuse-type gastric carcinoma cell lines (OCUM-12, HSC-39, and OCUM-2MLN). Overexpression of the dominant-negative form of BMP-2/4-specific type I receptor (ALK-3) in OCUM-12 and HSC-39 cells accelerated their growth in vivo. BMP-4 induced cell cycle arrest in these cells via p21 induction through the SMAD pathway. Moreover, overexpression of the constitutively active form of ALK-3 in HSC-39 and OCUM-2MLN cells suppressed the proliferation of these cells in vitro and in vivo. Our findings suggest that BMP-2 and BMP-4 function as potent tumor suppressors in diffuse-type gastric carcinoma.

A Case of Tuberous Sclerosis Complex with Renal Angiolipoma Who Has Symptom of Gross Hematuria

Tuberous sclerosis is a genetic disorder affecting cellular differentiation and proliferation, which results in hamartoma formation in many organs (eg, skin, brain, eye, kidney, and heart). Renal involvement is usually manifested by angiomyolipomas. Angiomyolipomas are benign tumors of vessels and are seen in up to 50-75% of patients. Spontaneous bleeding may be fatal but symptomatic complications are rare. Here in, we report a case of unilateral renal angiomyolipoma in a sixteen-yearold boy with tuberous sclerosis who had symptom of gross hematuria.

Facial Angiofibromas Associated with Tuberous Sclerosis

A 29-year-old woman presented with a long-standing history of yellow-orange papules on her nose and cheeks, skin-colored papules at the proximal nail fold of several toes, and a skin-colored plaque on her back. These findings were diagnosed as facial angiofibromas, periungual fibromas, and a shagreen patch, respectively. They are characteristic of tuberous sclerosis, an autosomal dominant disorder in which mutations in tumor suppressor gene TSC1 or TSC2 result in the formation of benign hamartomas throughout the body. Previous computed tomography of the brain had shown such hamartomas in the patient. Almost all patients with this condition have at least one . . .

Zebrafish model of tuberous sclerosis complex reveals cell-autonomous and non-cell-autonomous functions of mutant tuberin

SUMMARYTuberous sclerosis complex (TSC) is an autosomal dominant disease caused by mutations in either the TSC1 (encodes hamartin) or TSC2 (encodes tuberin) genes. Patients with TSC have hamartomas in various organs throughout the whole body, most notably in the brain, skin, eye, heart, kidney and lung. To study the development of hamartomas, we generated a zebrafish model of TSC featuring a nonsense mutation (vu242) in the tsc2 gene. This tsc2vu242 allele encodes a truncated Tuberin protein lacking the GAP domain, which is required for inhibition of Rheb and of the TOR kinase within TORC1. We show that tsc2vu242 is a recessive larval-lethal mutation that causes increased cell size in the brain and liver. Greatly elevated TORC1 signaling is observed in tsc2vu242/vu242 homozygous zebrafish, and is moderately increased in tsc2vu242/+ heterozygotes. Forebrain neurons are poorly organized in tsc2vu242/vu242 homozygous mutants, which have extensive gray and white matter disorganization and ectopically positioned cells. Genetic mosaic analyses demonstrate that tsc2 limits TORC1 signaling in a cell-autonomous manner. However, in chimeric animals, tsc2vu242/vu242 mutant cells also mislocalize wild-type host cells in the forebrain in a non-cell-autonomous manner. These results demonstrate a highly conserved role of tsc2 in zebrafish and establish a new animal model for studies of TSC. The finding of a non-cell-autonomous function of mutant cells might help explain the formation of brain hamartomas and cortical malformations in human TSC.

The Serine Protease HtrA1 Specifically Interacts and Degrades the Tuberous Sclerosis Complex 2 Protein

Hamartin and tuberin are products of the tumor suppressor genes TSC1 and TSC2, respectively. Mutations affecting either gene result in the tuberous sclerosis syndrome, a neurologic genetic disorder characterized by the formation of multiple benign tumors or hamartomas. In this study, we report the identification of TSC2, but not TSC1, as a substrate of HtrA1, a member of the human HtrA family proteins of serine proteases. We show the direct interaction and colocalization in the cytoplasm of HtrA1 and TSC2 and that HtrA1 cleaves TSC2 both in vitro and in vivo. Finally, we show that alterations in HtrA1 expression cause modifications in phosphorylation status of two downstream targets of TSC2: 4E-BP1 and S6K. Our data suggest that, under particular physiologic or pathologic conditions, HtrA1 degrades TSC2 and activates the downstream targets. Considering that HtrA1 levels are significantly increased during embryogenesis, we speculate that one of the targets of HtrA1 activity during fetal development is the TSC2-TSC1 pathway.

Tuberous Sclerosis Complex 2 (TSC2) Regulates Cell Migration and Polarity through Activation of CDC42 and RAC1

The phosphatidylinositol 3-kinase (PI3K)/AKT pathway plays important roles in regulating cell motility. TSC2, a downstream target of AKT, is a central player in negatively controlling cell proliferation and protein translation through suppressing the activity of mTOR (mammalian target of rapamycin). However, the function of TSC2 in regulating cell migration remains unclear. Here, we show that TSC2 plays a critical role in the control of cell spreading, polarity, and migration. TSC2-deficient fibroblast cells were impaired in their ability to spread and alter actin cytoskeleton upon stimulation with insulin-like growth factor-1. Using scratch-induced polarization assay, we demonstrate that TSC2((-/-)) fibroblast cells polarized poorly toward the wound compared with wild-type cells. Similarly, knockdown of TSC2 expression in colon cancer cells resulted in a marked decrease in cell motility. Functionally, the activation of CDC42- and RAC1-GTPase was largely reduced in TSC2 knock-out fibroblast and TSC2 knockdown cancer cells. Furthermore, overexpression of an activating p110alpha mutant or short term rapamycin treatment rescued the cell polarization defect in TSC2((-/-)) fibroblast cells. Concurrently, the activation of CDC42 and RAC1 increased. The defect in cell migration and CDC42 and RAC1 activation was reversed by reintroducing TSC2 back into TSC2((-/-)) fibroblast cells. Taken together, we identified a novel role of TSC2 in controlling cell polarity and migration by regulating CDC42 and RAC1 activation.

Everolimus for subependymal giant-cell astrocytomas (SEGAs) in tuberous sclerosis (TS).

2004 Background: TS is a potentially devastating disorder characterized by hamartoma formation in multiple organ systems. SEGAs develop in 5-15% of TS patients and represent a significant medical risk, including the potential for sudden death secondary to acute hydrocephalus (as a result of their location adjacent to the foramen of Monro). Neurosurgical resection is the current standard treatment and no effective alternative has been identified. Methods: Patients ≥3 years with a definitive TS diagnosis and evidence of serial SEGA growth (on MRI) were eligible for this prospective, open-label, phase II study. The primary efficacy endpoint was change in SEGA volume from baseline to 6 months (mo). Everolimus dose (3 mg/m2 QD orally) was titrated subject to tolerability to achieve target trough concentrations of 5-15 ng/mL. Results: 28 patients were enrolled between 1/07 and 12/08; median duration of treatment was 22 mo (range 5-34). Everolimus was associated with a clinically meaningful reduction in SEGA volume (p<0.001); marked reductions were seen within the initial 3 mo and subsequently sustained or further improved (see table). No patient developed new lesions, worsening hydrocephalus, or worsening signs or symptoms of increased intracranial pressure; none required surgical resection or other therapy for SEGA. Of 16 patients for whom video-EEG data were available, 9 experienced decreases in seizure frequency (across all types of seizure), 6 reported no change (all were event-free at both timepoints), and 1 patient experienced an increase (median change -1.0, p=0.012). Grade 3 adverse drug reactions were single cases of sinusitis, pneumonia, viral bronchitis, tooth infection, stomatitis, and leukopenia; no grade 4 events were reported. Conclusions: Everolimus is effective in TS-associated SEGA with 78% of patients achieving the prespecified ≥30% reduction at 6 mo; it is also well tolerated and offers a viable alternative to surgical resection. SEGA volume (independent central review) % reduction from baseline, n (%) 3 mo n=26 6 mo n=27 12 mo n=26 18 mo n=18 24 mo n=8 ≥50% 10 (38) 9 (33) 9 (35) 8 (44) 3 (38) ≥30% 17 (65) 21 (78) 20 (77) 12 (67) 6 (75) >0% 25 (96) 27 (100) 26 (100) 16 (89) 8 (100) No change 0 0 0 1 (6) 0 Growth 1 (4) 0 0 1 (6) 0 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis Novartis