Ungual Fibromas Research Articles

Malignant tumors in tuberous sclerosis complex: a case report and review of the literature

BackgroundTuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic disease that arises from TSC1 or TSC2 genetic mutations. These genetic mutations can induce the development of benign tumors in any organ system with significant clinical implications in morbidity and mortality. In rare instances, patients with TSC can have malignant tumors, including renal cell carcinoma (RCC) and pancreatic neuroendocrine tumor (PNET). It is considered a hereditary renal cancer syndrome despite the low incidence of RCC in TSC patients. TSC is typically diagnosed in prenatal and pediatric patients and frequently associated with neurocognitive disorders and seizures, which are often experienced early in life. However, penetrance and expressivity of TSC mutations are highly variable. Herein, we present a case report, with associated literature, to highlight that there exist undiagnosed adult patients with less penetrant features, whose clinical presentation may contain non-classical signs and symptoms, who have pathogenic TSC mutations.Case presentationA 31-year-old female with past medical history of leiomyomas status post myomectomy presented to the emergency department for a hemorrhagic adnexal cyst. Imaging incidentally identified a renal mass suspicious for RCC. Out of concern for hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome, the mass was surgically removed and confirmed as RCC. Discussion with medical genetics ascertained a family history of kidney cancer and nephrectomy procedures and a patient history of ungual fibromas on the toes. Genetic testing for hereditary kidney cancer revealed a 5’UTR deletion in the TSC1 gene, leading to a diagnosis of TSC. Following the diagnosis, dermatology found benign skin findings consistent with TSC. About six months after the incidental finding of RCC, a PNET in the pancreatic body/tail was incidentally found on chest CT imaging, which was removed and determined to be a well-differentiated PNET. Later, a brain MRI revealed two small cortical tubers, one in each frontal lobe, that were asymptomatic; the patient’s history and family history did not contain seizures or learning delays. The patient presently shows no evidence of recurrence or metastatic disease, and no additional malignant tumors have been identified.ConclusionsTo our knowledge, this is the first report in the literature of a TSC patient without a history of neurocognitive disorders with RCC and PNET, both independently rare occurrences in TSC. The patient had a strong family history of renal disease, including RCC, and had several other clinical manifestations of TSC, including skin and brain findings. The incidental finding and surgical removal of RCC prompted the genetic evaluation and diagnosis of TSC, leading to a comparably late diagnosis for this patient. Reporting the broad spectrum of disease for TSC, including more malignant phenotypes such as the one seen in our patient, can help healthcare providers better identify patients who need genetic evaluation and additional medical care.

Tuberous Sclerosis Complex in a 20-year-old Female: Delayed Recognition and Life-threatening Outcomes

Tuberous sclerosis complex (TSC) is a rare, autosomal dominant multisystem disorder affecting the brain, heart, kidneys, lungs, and skin leading to significant morbidity and mortality. We report a case of TSC and highlight the need for prompt diagnosis and proper surveillance to minimize life-threatening complications. A 20-year-old female presented with facial and ungual papulonodular lesions 4 years after being diagnosed with epilepsy at the age of eight. No family history of genetic diseases was reported. Eight years later, the patient developed recurrent cough, shortness of breath, and blurring of vision. Biopsy of facial and digital nodule showed angiofibroma and ungual fibroma (Koenen tumor), respectively. Chest computed tomography scan revealed extensive cystic lesions diffusely scattered throughout the entire lung parenchyma suggestive of lymphangioleiomyomatosis. Cranial MRI revealed cortical and subependymal tubers, compatible with TSC. The patient had multidisciplinary management. However, her symptoms progressed, and she eventually succumbed to death. Cutaneous lesions such as facial angiofibromas and ungual fibromas along with multisystemic manifestations should alarm the clinician to TSC. Given its highly variable expressivity, awareness of different TSC-associated signs and symptoms is essential for prompt diagnosis, proper treatment, disease monitoring, and early recognition of TSC complications.

The tuberous sclerosis complex: a review of the literature

Tuberous sclerosis complex (TSC) is a neurocutaneous autosomal dominant genetic disorder characterized by mutations in the TSC1 and TSC2 genes, this leads to dysregulation of the mechanistic target of rapamycin (mTOR) pathway resulting in cellular hyperplasia and the formation of benign tumors in various organs, including the brain and skin. Clinical manifestations encompass a wide range of mainly neurological and dermatological symptoms, often presenting during early childhood and posing diagnostic challenges due to phenotypic variability. Recent advancements in diagnostic criteria, genetic testing, and imaging techniques have facilitated earlier diagnosis and increased disease incidence awareness. Neurologically, TSC commonly presents with cortical tubers, subependymal nodules (SENs), and epilepsy, with seizure control being paramount in preventing long-term neurodevelopmental sequelae. Dermatologically, hypomelanotic macules, facial angiofibromas, and ungual fibromas are hallmark features, often causing significant psychological distress due to disfigurement. Management of TSC requires a multidisciplinary approach, with emerging therapies such as mTOR inhibitors showing promise in addressing both neurological and dermatological manifestations. Early intervention, including epilepsy surgery and targeted treatments for skin lesions, is essential for optimizing outcomes and improving the quality of life for patients with TSC. Continued research into novel therapeutic modalities holds potential for further enhancing the management and prognosis of this complex disorder.

Giant cell angiofibroma of gingiva in tuberous sclerosis complex: a case report and literature review

BackgroundTuberous sclerosis complex (TSC) is a rare, complex genetic disorder characterized by hamartomas and neoplastic lesions in various organ systems. With the development of radiology and gene testing, the diagnostic criteria for TSC were updated in 2012 at the International Consensus Conference. Intraoral fibromas have long been associated with TSC. However, the incidence of giant cell angiofibroma (GCA) in TSC patients is extremely rare. Here, we report the first case of GCA in the gingival tissue of a patient with TSC.Case presentationA 41-year-old woman first visited the Department of Oral and Maxillofacial Surgery, Chonnam National University Dental Hospital, complaining of gingival enlargement. Clinical examination revealed several manifestations associated with TSC, including intraoral fibromas, facial angiofibromas, dental enamel pits, ungual fibromas, “confetti” skin lesions, hypomelanotic macules, and a shagreen patch. Intraoral examination revealed a 6.0 × 5.0 cm gingival overgrowth on the left mandible. Surgical excision was performed, and subsequent histopathological examination confirmed the diagnosis of GCA. There was no evidence of recurrence within the 24- months of surgery.ConclusionsWe report the first case of GCA in the gingival tissue of a patient with TSC. This report would contribute to an improved understanding of this rare disease. However, further case reports are necessary to clarify the relationship between GCA and TSC.

Tuberous sclerosis complex, Clinic and pathology manifestations, Mini -review

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome that affects almost all of the organs of the body, including the brain, heart, lungs, liver, and kidneys. Brain tumors in TSC patients include cortical tubers, subependymal nodules (SENs), and Subependymal giant cell astrocytomas (SEGAs). Seizures that occur in 92% of patients with TSC are an important cause of sudden deaths in them. Other organ involvement includes renal angiomyolipomas, lymphangioleiomyomatosis, cardiac rhabdomyomas, and cutaneous manifestations (hypomelanotic macules, angiofibroma, ungual fibromas, shagreen patch, and ‘confetti’ skin lesions). There is a criterion for tuberous sclerosis complex that consists of 11 major and 6 minor clinical features that diagnosis occurs based on it. The best way for a definitive diagnosis of TSC in a patient is by using genetic tests and histopathology. Immunohistochemistry is a helpful method in confirming the diagnosis of brain tumors in TSC. Immunostaining of SEGA shows positivity for GFAP and S-100 protein while neurofilament and synaptophysin are negative. Ki-67, which indicates nuclear proliferation, has a low proliferation index in immunostain. In an aggressive tumor, hydrocephalus, rising intracranial pressure and focal neurologic deficit, surgery is a necessity and can improve outcomes. Brain and kidney involvement in this disease is life-threatening. Brain involvement in these patients can lead to extensive neuropsychological complications, so the aim of this study is a concise review of the variable manifestations of this disease with a focus on the histopathological findings of brain involvement.

Late diagnosis of tuberous sclerosis: a case report

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by the formation of hamartomas in organ systems such as the brain, skin, kidneys and lungs. Patients with TSC are usually diagnosed early in life. However, in some cases, the diagnosis is delayed until adulthood because various manifestations occur at various times throughout an individual's life. In this regard, we present the case of a female patient diagnosed at the beginning of the seventh decade of life. The patient had a history of seizures and showed clinical findings on the skin (facial angiofibromas, ungual fibromas, 'Confetti-like' skin lesions, shagreen patch), brain (cortical tubers), heart (cardiac rhabdomyomas), kidneys (angiomyolipomas) and a positive genetic test for mutations in TSC2, fulfilling the diagnostic criteria. We compared the differences between manifestations in patients diagnosed during childhood and adulthood. Knowledge of the clinical spectrum of TSC allows early identification.

469 Altered expression of genes regulating mTOR and other signaling pathways in skin tumors from patients with tuberous sclerosis complex

Individuals with tuberous sclerosis complex (TSC) develop tumors in multiple organs due to pathogenic variants in TSC1 or TSC2, with skin tumors showing mTOR activation and aberrant cell growth. To identify transcriptional signatures and dysregulated signaling pathways that are shared in different types of TSC skin tumors, we performed RNAseq on 58 samples of fibroblast-like cells grown from TSC skin tumors (27 angiofibromas, 11 fibrous cephalic plaques, 10 ungual fibromas, 8 shagreen patches, 2 oral fibromas) and 28 samples of fibroblasts from patient normal appearing skin, in patients whose blood DNA showed germline variants in TSC2 in 14, TSC1 in 1, mosaicism in 3, and no mutation identified in 3.

Diagnosis and genotype-phenotype correlation in patients with PKD1/TSC2 contiguous gene deletion syndrome.

Deletions involving the TSC2 and PKD1 genes lead to tuberous sclerosis complex (TSC) and autosomal dominant polycystic kidney disease (ADPKD), which is known as TSC2-PKD1 contiguous gene deletion syndrome (PKDTS). PKDTS leads to severe symptoms and death. There are few reported cases of PKDTS, the phenotypic descriptions are poor, and detailed statistics and descriptions of the time of onset and prognosis of PKDTS are lacking. This is the first study to report on the clinical data of PKDTS patients in China. We analyzed all cases including Chinese individuals and summarized the clinical manifestations and genetic characteristics. Our study was the first to use a combination of exome sequencing and multiplex ligation-dependent probe amplification (MLPA) to screen and diagnose PKDTS. We found that many PKDTS patients have the following: multiple renal cysts; angiofibromas (≥ 3) or fibrous cephalic plaque; subependymal nodules; seizures; intellectual disability. PKDTS develops into polycystic kidney disease from before birth to 17 years old and the time of occurrence of end-stage renal disease or dialysis was 21.62 ± 12.87 years of age, which was significantly earlier than in ADPKD caused by PKD1 mutation. Compared with non-Chinese individuals of diverse ancestry, Chinese people have significant differences in the clinical characteristics, including ungual fibromas (≥ 2), and shagreen patch. Five novel large deletions were identified in Chinese. We found no relationship between the clinical phenotype and the genotype. We combined exome sequencing with MLPA to develop a diagnostic method for PKDTS.

Analysis of Clinical Features and Next-Generation Sequencing of 12 Tuberous Sclerosis Families in China.

BackgroundTuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disease with systemic organ involvement. So far, only a few TSC families in China have been reported. Therefore, more data on the clinical and genetic features of TSC families are required.Materials and MethodsWe retrospectively analyzed 12 TSC family probands and their family members. Next-generation sequencing (NGS) has been applied to confirm the type of TSC mutation along with a detailed physical examination.ResultsIn this study, twenty-seven patients in 12 TSC families were reported, including 12 male and 15 female patients, aged 8–67 years. Skin lesions were detected among all patients with TSC, including 25 cases of facial angiofibromas, 18 cases of hypomelanotic macules, 15 cases of ungual fibromas, and 13 cases of shagreen patch. Other clinical features were also revealed: 14 cases of renal angiomyolipoma, 6 cases of subependymal nodules (SENs), and 3 cases of lymphangioleiomyomatosis. All twenty-seven patients with TSC were tested by NGS. Totally, TSC2 mutations were reported in 19 cases (7 frameshift mutations, 10 nonsense mutations, and 2 missense mutations), TSC1 mutations were reported in 4 cases (4 nonsense mutations), and 4 cases were genetically negative. The novel causal mutations (TSC2: c.208dup, c.1874C > G, c.1852del) identified in three families were first reported in TSC.ConclusionOur findings expand the mutation spectrum of patients with TSC in China. The clinical characteristics can vary among patients with TSC with the same pathogenic mutation. The genetic results and summary of clinical features of 12 TSC families contribute to a more accurate diagnosis and further genetic counseling.

Histological Patterns of Skin Lesions in Tuberous Sclerosis Complex: A Panorama.

Tuberous Sclerosis Complex (TSC) is a multisystem genetic disease characterized by cutaneous and extracutaneous hamartomas. The diagnosis is based on the association of major and minor criteria, defined by a consensus conference updated in 2012. The clinical examination of the skin is crucial because seven diagnostic criteria are dermatological: four major (hypomelanotic macules, angiofibroma or fibrous cephalic plaques, ungual fibromas, shagreen patches) and three minor criteria (confetti skin lesions, dental enamel pits, intraoral fibromas). Skin biopsy is commonly performed to assert the diagnosis of TSC when the clinical aspect is atypical. Histopathology of TSC cutaneous lesions have been poorly reported until now. In this article, we review the histologic features described in the literature and share our experience of TSC skin biopsies in our pediatric hospital specialized in genetic disorders. Both hypomelanotic lesions and cutaneous hamartomas (angiofibroma/fibrous cephalic plaques, ungual fibromas, shagreen patches) are discussed, including the recent entity called folliculocystic and collagen hamartoma, with a special emphasis on helpful clues for TSC in such lesions.

Molecular-Genetic Characteristics and Genotype-Phenotype Correlations in Bulgarian Patients with Tuberous Sclerosis Complex

Abstract Objective The aim of the study was to determine the molecular-genetic characteristics of the autosomal dominant systematic disorder Tuberous Sclerosis Complex (TSC1 and TSC2) in Bulgarian patients and to derive some genotype-phenotype correlations. Material and Methods In total 42 patients/families with suspected clinical diagnosis of TSC were analyzed. We used direct sequencing and MLPA for the TSC1 and TSC2 gene analysis. Results In 38 families (90.5%) we confirmed the suspected clinical diagnosis – 15 with TSC1 (35.7%) and 23 (54.8%) with TSC2. In 4 families (9.5%) pathogenic variants were not found. In all 38 patients with proven diagnosis of TSC, we found 38 different mutations, 15 of which (39%) were detected for the first time by our research group. The mutation “hotspots“ in TSC1 gene are exons 9, 15, 17 and 18, where 73% of the TSC1 mutations are localized, while the TSC2 gene mutation “hotspots“ are exons 13 and 34, with 22% of the mutations situated there. In the TSC2 patients the common clinical findings include subcortical tubers, epilepsy with generalized tonic-clonic seizures, subependymal giant cell astrocytoma, facial angiofibromas, ungual fibromas, cardiac rhabdomyomas and renal angiomyolipomas, while in the TSC1 patients typically cortical tubers, cortical dysplasia and subependymal nodules were registered. In patients with aggressive frameshift and nonsense TSC1 and TSC2 mutations commonly hypomelanotic macules, cortical and subcortical tubers, cortical dysplasia, epilepsy with different types of seizures were found. Renal angiomyolipomas and cysts were detected mainly in patients with large deletions. Shagreen patches and intellectual disability were typically registered in equal degree in patients with frameshift, nonsense and missense mutations. Conclusion Although some genotype-phenotype correlations were derived, there is a great inter- and intrafamilial clinical variability in TSC, so it is impossible to predict the course of the disease on the basis of the detected molecular defect. The obtained results helped us to develop a diagnostic algorithm for proper molecular-genetic diagnostics which permits adequate genetic counseling, prophylaxis and treatment in the affected TSC families.

Pulmonary lymphangioleiomyomatosis (LAM)

Lymphangioleiomyomatosis (LAM) is arare lung disease that mostly occurs in female patients. A total of 200-400 people are assumed to be infected in Germany. Asporadic form and aform associated with the tuberous sclerosis complex (TSC) can be separated. Mutations of the TSC‑1 and TSC‑2 genes are relevant. Morphologically, pulmonary multicysts and marginal micronodal proliferations of LAM cells are characteristic. Combinations with renal angiomyolipoma are typical and, in cases with TSC glioma, facial angiofibroma and ungual fibroma are seen. Prognosis is favorable (10-year survival: 80%) and with the use of mTORC1 inhibitors it could be improved. Lung transplantation can be considered in some cases.

Dermoscopic findings in a case of multiple subungual fibromas

Periungual and subungual fibromas, also known as Koenen tumors, are diagnostic findings of tuberous sclerosis. The clinical appearance and histological features that characterize ungual fibromas are well defined. However, dermoscopic findings of these benign tumors have not been reported previously. Here we report a rare presentation of multiple subungual fibromas of all fingers in a developmentally delayed patient with tuberous sclerosis along with the dermoscopic features of the ungual tumors.

Squamous cell carcinoma–like ungual fibroma as early diagnostic indicators of tuberous sclerosis complex in an elderly patient

Squamous cell carcinoma–like ungual fibroma as early diagnostic indicators of tuberous sclerosis complex in an elderly patient

Tuberous Sclerosis–Associated Renal Neoplasm

A man in his thirties presented with bilateral renal masses and well-controlled hypertension. He had a history of resection of a brain lesion in early childhood. Imaging studies did not reveal cystic lung disease. Bilateral nephrectomies were performed because of end-stage renal disease, and both kidneys were replaced by fibrotic and lobulated masses. Histopathological examination revealed extensive involvement by angiomyolipoma bilaterally. What syndrome should this patient be screened for, and what are some other common associated features?a.Birt-Hogg-Dubé syndrome: benign tumors of the skin and spontaneous pneumothorax secondary to cystic lung diseaseb.von Hippel-Lindau disease: central nervous system hemangioblastomas and pheochromocytomasc.Li-Fraumeni syndrome: osteosarcoma, adrenocortical carcinoma, and central nervous system tumorsd.Tuberous sclerosis complex: subependymal giant cell astrocytomas, cardiac rhabdomyomas, and lymphangioleiomyomatosis Answer: d. Tuberous sclerosis complex: subependymal giant cell astrocytomas, cardiac rhabdomyomas, and lymphangioleiomyomatosis Tuberous sclerosis complex is associated with renal manifestations including renal angiomyolipomas and a wide spectrum of renal neoplasia that have variable morphological features.1Guo J. Tretiakova M.S. Troxell M.L. et al.Tuberous sclerosis-associated renal cell carcinoma: a clinicopathologic study of 57 separate carcinomas in 18 patients.Am J Surg Pathol. 2014; 38: 1457-1467Crossref PubMed Scopus (129) Google Scholar Two major diagnostic features or a combination of 1 major and at least 2 minor diagnostic features are required to establish a clinical diagnosis.2Henske E.P. Jóźwiak S. Kingswood J.C. Sampson J.R. Thiele E.A. Tuberous sclerosis complex.Nat Rev Dis Primers. 2016; 2: 16035Crossref PubMed Scopus (214) Google Scholar Major diagnostic criteria for tuberous sclerosis include hypomelanotic macules (≥3 of ≥5 mm in diameter), angiofibromas (≥3) or fibrous cephalic plaques, ungual fibromas (≥2), shagreen patches, multiple retinal hamartomas, cortical dysplasias, subependymal nodules, subependymal giant cell astrocytomas, cardiac rhabdomyomas, lymphangioleiomyomatosis, and angiomyolipomas (≥2). Tuberous sclerosis complex is an autosomal dominant disorder associated with loss-of-function alterations in TSC1 and TSC2 genes (for expansion of gene symbols, use search tool at www.genenames.org). von Hippel-Lindau disease, secondary to germline alterations in the VHL gene, is associated with clear cell renal cell carcinoma, central nervous system hemangioblastoma, and pheochromocytoma. Li-Fraumeni syndrome, secondary to germline alterations in the TP53 gene, is associated with osteosarcoma, adrenocortical carcinoma, and central nervous system tumors. Finally, Birt-Hogg-Dubé syndrome, secondary to germline alterations in the FLCN gene, is associated with hybrid renal tumors, benign tumors of the skin, and spontaneous pneumothorax secondary to cystic lung disease.

Tuberous Sclerosis Complex Associated Lymphangioleiomyomatosis Presenting with Spontaneous Pneumothorax and Renal Angiomyolipomas

Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder manifested by involvement of multisystem including skin, central nervous system, heart, kidneys and eyes. Lymphangioleiomyomatosis (LAM) is also a multisystem disorder that primarily affects the lungs. We report a case of tuberous sclerosis complex associated lymphangio-leiomyomatosis (TSC-LAM) in a 26-year-old female patient who was presented with spontaneous pneumothorax and renal angiomyolipomas. In clinical examination; We found multiple angiofibromas over her face, shagreen patches over upper and lower back and ungual fibromas in both fingers and toes. HRCT of chest revealed right sided pneumothorax with multiple thin walled cysts in both lungs. Ultrasonogram (USG) and Computer Tomography (CT) scan of abdomen revealed bilateral angiomyolipomas. We managed her pneumothorax with intercostal chest tube drainage and oxygen inhalation.
 Bangladesh Med J. 2019 May; 48 (2): 51-54

LONG-TERM FOLLOW-UP OF MEDIASTINAL PERIVASCULAR EPITHELIOID CELL TUMOR

SESSION TITLE: Lung Cancer 3 SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Perivascular Epithelioid Cell Tumors (PEComas) are rare mesenchymal tumors associated with tuberous sclerosis complex. The prognosis of PEComa are unpredictable. Due to the rarity of these tumors, mediastinal PEComa’s present a diagnostic & therapeutic challenge. Once identified, these patients require long-term follow-up due to uncertainty with treatment response. The purpose of this case is to demonstrate the response to treatment. CASE PRESENTATION: A 27 year old Indian male presents to the hospital in 2010 with a 1 month history of fever, left sided chest pain, dyspnea and cough. Past medical history was unremarkable. Surgical history consisted of excised occipital fibrolipoma many years ago. Family history was negative for malignancy or lung disease. Positive exam findings include shagreen patch on the left lateral neck, hypomelanotic ash leaf spot on the sternum and ungual fibroma. Chest X-ray revealed extensive infiltrate in the left lower lobe with CT chest confirming bilateral bullous emphysema and necrotizing pneumonia. It also detected 6.7 cm subcarinal mass. He subsequently underwent right thoracotomy on 3-23-2010, where a large mass was identified with a well-encapsulated overlying pleural envelope. H&E staining showed spindle cell neoplasm. Biopsy samples were immunoreactive and positive for actin, desmin, and HMB-45 and negative for S-100, CD34, kit (CD117), Melan-A, and h-caldesmon. Tumor necrosis factor was not tested. Diagnosis of PEComa was made based on immunoreactivity. Patient was also diagnosed with Tuberous Sclerosis complex due to constellation of physical findings. He declined genetic testing due to cost.Patient was started on Sirolimus for his PEComa in July 2010 and underwent serial CT scans at 3 month intervals. He has been followed closely for last 8 years and has tolerated Sirolimus well without any side effects. He has shown steady clinical and radiographic response to Sirolimus without any evidence of metastasis. His last CT Chest showed tumor size reduction to 1.9 cm in December 2017. He has been treated surgically for left spontaneous pneumothorax due to his bullous emphysema recently in December 2017 DISCUSSION: Treatment of PEComa with mTor inhibitors like Sirolimus, has been described with variable results. In this case, primary PEComa arising from the lung showed significant radiographic improvement in the tumor size. CONCLUSIONS: This case illustrates an example of a rare neoplasm associated with Tuberous Sclerosis Complex, which poses a diagnostic and therapeutic challenge. Sirolimus and other mTOR inhibitors show promise as potential treatment option for these tumors. Long term follow-up and prospective studies are needed for such neoplasms. Reference #1: Wagner AJ, Malinowska-Kolodziej I, Morgan JA, et al. Clinical Activity of mTOR Inhibition With Sirolimus in Malignant Perivascular Epithelioid Cell Tumors: Targeting the Pathogenic Activation of mTORC1 in Tumors. Journal of Clinical Oncology. 2010;28(5):835-840. https://doi.org/10.1200/JCO.2009.25.2981. DISCLOSURES: No relevant relationships by Riju Dasgupta, source=Web Response No relevant relationships by Asok Dasgupta, source=Web Response No relevant relationships by Patrick Elwood, source=Web Response No relevant relationships by Chelsea Leipold, source=Web Response No relevant relationships by Sivaraman Sivaswami, source=Web Response No relevant relationships by Paresh Timbadia, source=Web Response

Tuberous sclerosis complex

Clinical characteristics Tuberous sclerosis complex (TSC) involves abnormalities of the skin (hypomelanotic macules, confetti skin lesions, facial angiofibromas, shagreen patches, fibrous cephalic plaques, ungual fibromas); brain (subependymal nodules, cortical dysplasias, and subependymal giant cell astrocytomas [SEGAs], seizures, intellectual disability / developmental delay, psychiatric illness); kidney (angiomyolipomas, cysts, renal cell carcinomas); heart (rhabdomyomas, arrhythmias); and lungs (lymphangioleiomyomatosis [LAM], multifocal micronodular pneumonocyte hyperplasia). Central nervous system tumors are the leading cause of morbidity and mortality; renal disease is the second leading cause of early death. Diagnosis/testing The diagnosis of TSC is established in a proband with one of the following: Two major clinical features One major clinical feature and two or more minor features Identification of a heterozygous pathogenic variant in TSC1 or TSC2 by molecular genetic testing Management Treatment of manifestations: For enlarging SEGAs: mTOR inhibitors; neurosurgery when size causes life-threatening neurologic symptoms. For seizures: vigabatrin and other anti-seizure medication, and on occasion, epilepsy surgery. For renal angiomyolipomas >4 cm, or >3 cm and growing rapidly: mTOR inhibitors are the recommended first line of therapy with secondary therapy options being embolization, renal sparing surgery, or ablative therapy. For facial angiofibromas: topical mTOR inhibitors. For symptomatic cardiac rhabdomyomas: surgical intervention or consideration of mTOR inhibitor therapy. For LAM: mTOR inhibitors. Prevention of secondary complications: For those on vigabatrin therapy, vision testing within four weeks of therapy initiation, at three-month intervals while on treatment, and three to six months after treatment is discontinued. Surveillance: Brain MRI every one to three years in asymptomatic individuals with TSC younger than age 25 years to monitor for new occurrence of SEGAs; those with asymptomatic SEGA in childhood should continue to be imaged periodically in adulthood; for those with large or growing SEGA or SEGA causing ventricular enlargement, more frequent brain MRIs as deemed clinically appropriate; screening for TSC-associated neuropsychiatric disorder (TAND) at least annually with comprehensive formal evaluation for TAND at key developmental time points; EEG in individuals with known or suspected seizure activity; MRI of the abdomen to assess for progression of angiomyolipoma and renal cystic disease every one to three years; assess renal function (glomerular filtration rate and blood pressure) at least annually; echocardiogram every one to three years in asymptomatic infants and children with cardiac rhabdomyomas until regression is documented; clinical screening for LAM symptoms (exertional dyspnea and shortness of breath) at each clinic visit in women older than age 18 years or those who report respiratory symptoms; high-resolution computed tomography (HRCT) every five to ten years in asymptomatic individuals at risk for LAM (adult females age >18 years) even when there are no signs of LAM on baseline examination; annual pulmonary function testing and HRCT every two to three years for individuals with lung cysts detected by HRCT; annual dermatologic examination; dental examination every six months; annual ophthalmology evaluation in those with previously identified ophthalmologic lesions or vision symptoms. Agents/circumstances to avoid: Smoking; estrogen use; nephrectomy. Evaluation of relatives at risk: Identifying affected relatives enables monitoring for early detection of problems associated with TSC, which leads to earlier treatment and better outcomes. Genetic counseling TSC is inherited in an autosomal dominant manner. Two thirds of affected individuals have TSC as the result of a de novo pathogenic variant. The offspring of an affected individual are at a 50% risk of inheriting the pathogenic variant. If the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Dermatological manifestations of tuberous sclerosis complex (TSC).

Tuberous sclerosis complex (TSC) is a genetic multisystem disorder with prominent skin involvement that frequently occurs in early childhood. Dermatologic manifestations include facial angiofibromas, hypomelanotic macules, fibrous cephalic plaques, shagreen patches, and ungual fibromas. The International TSC Consensus Conference in 2012 provided guidelines for standardized baseline evaluation and follow-up. Detailed clinical dermatological evaluation at the time of diagnosis and annual skin examination is recommended for both pediatric and adult populations. The onset of dermatological manifestations is clearly age-related. However, dermatologists also have to assess for clinical manifestations beyond their own specialty. With advances in genetics and the advent of mTORC1 inhibitors, new specific therapeutic options have become available for TSC patients with skin manifestations. Early intervention is commonly recommended for symptomatic, rapidly evolving, disfiguring, or debilitating lesions. The consensus guidelines recommend "treatment as appropriate for the lesion and clinical context" and suggest the use of surgical excision, laser therapy, or topical mTORC1 inhibitors. Topical mTORC1 inhibitors present a useful option for TSC-associated skin lesions, particularly in medically complex patients. They may prevent or reduce the risks of subsequent surgeries and permanent scarring.

Long-term treatment of cutaneous manifestations of tuberous sclerosis complex with topical 1% sirolimus cream: A prospective study of 25 patients

Data on long-term topical sirolimus treatment of the cutaneous manifestations of tuberous sclerosis complex are rare. To evaluate the long-term benefit and tolerance of topical 1% sirolimus in tuberous sclerosis complex. In this 18-month prospective single-center study, 1% sirolimus cream was applied daily to facial angiofibromas (FAs), fibrous cephalic plaques (FCPs), shagreen patches, hypomelanotic macules, and ungual fibromas. After complete clearance (CC) of FAs, we evaluated a maintenance protocol of 3 applications weekly. Twenty-five patients were enrolled. Fifty percent obtained CC of FAs within 9months. Of 7 patients with CC (58%) who were following the maintenance protocol, 6 relapsed within 7months and 1 was still responding at 1year. Of 16 patients with FCPs, 7 (44%) remained stable at 12months and 9 (56%) improved after 3 to 9months of treatment. Only 1 of 5 patients treated for shagreen patches showed improvement at 12months. Treatment was well tolerated with no serious adverse events. The small number of patients was a limitation. Topical 1% sirolimus applied daily produced positive responses in treatment of FAs, FCPs, and facial hypomelanotic macules and was well tolerated. A 3-times-weekly maintenance protocol did not prevent FA relapses.