Involvement In Tuberous Sclerosis Research Articles

Exploring Cardiovascular Involvement in Tuberous Sclerosis: Insights for Pediatric Clinicians.

Tuberous sclerosis is a rare genetic disorder involving mainly the nervous and cardiovascular systems. The early recognition of the cardiovascular manifestations by the pediatrician allows an appropriate management and therefore enhances the quality of life of the affected children. Cardiac rhabdomyomas and the associated arrhythmias are the first cardiac features and they might represent a diagnosis challenge given their wide spectrum of clinical manifestations. We aimed to provide the paediatric practitioners with current knowledge regarding the cardiovascular complications in children with tuberous sclerosis. We overviewed the antenatal and postnatal evolution of cardiovascular manifestations, the systematic screening and long-term follow-up strategy of cardiac rhabdomyomas and arrhythmias in children with tuberous sclerosis.

DIFFERENTIATION OF RETINAL ASTROCYTIC HAMARTOMA FROM OTHER RETINAL NEOPLASMS: A CASE REPORT

Astrocytic retinal hamartoma (phacoma, astrocytoma) is a benign tumor, formed through proliferation of glial astrocytes and blood vessels of the sensory part of the retina. For the first time, eye involvement in tuberous sclerosis (TS) was described by J. van der Hoeva, Dutch ophthalmologist in 1921. A characteristic glial tumor is still considered a classic manifestation of this disease, however, retinal astrocytoma can be observed in practically healthy young people or children. We present the case of a 19-year-old woman diagnosed with multiple retinal hamartomas in the right eye. In addition to ophthalmoscopy, we used the additional diagnostic methods to determine the form of hamartomas (calcined or uncalcined) and differentiate astrocytic retinal hamartoma from other tumors of the retina and choroid as well as to exclude pathological changes in the central nervous system.

Cutaneous lesions and visceral involvement of tuberous sclerosis: First report in North of Iran

Tuberous sclerosis (TS) is an autosomal dominant disorder with a significant range of clinical expressions. The involvement of vital organs, such as the brain, kidney, heart and lung is the main cause of death in patients with TS. The aim of this study is to summarize the characteristic cutaneous features and common extracutaneous involvement of TS, which are helpful to the early detection of visceral involvement. The analyzed clinical data from 10 patients with TS included those from detailed history, physical and dermatological examination, cranial computed tomography and magnetic resonance imaging, abdominal ultrasonography, chest roentgenography, and ophthalmologic examination. The skin, brain and electroencephalography were involved frequently in TS patients. Hypomelanotic macules were the most common and earliest cutaneous lesions. There were two facial angiofibromas and no Shagreen's patch in our patients. Cranial computed tomography showed a high positive rate including periventricular and Monro foramen calcification in TS patients. Hypsarrhythmia was the most common abnormality on electroencephalography background. Cutaneous features of TS are helpful in the early diagnosis of the disease. Hypomelanotic macules are especially important for patients with epilepsy or babies whose number of hypomelanotic macules is more than three. Cranial computed tomography is of great value in the diagnosis of TS. The involvement of visceral organs such as the brain and kidney should be considered in TS patients.

Prenatal Diagnosis of Intracranial Tumors and the Difficulties in Prognostication: A Report of Three Cases

ABSTRACTPrenatal diagnosis of intracranial tumors generally implies a poor prognosis. We present three such cases, where prognostication was difficult. We attempted to correlate our prenatal counseling with postnatal follow-up/postabortal diagnosis. In the first case, tumor was diagnosed at 37 weeks. Ultrasound and fetal/neonatal MRI suggested a malignant intraventricular tumor. Anticipating guarded prognosis, parents refused neurosurgical intervention. At 1 year, child has normal neurodevelopment. Further magnetic resonance imagings (MRIs) show tumor shrinkage, pointing to a benign tumor. In case two, a choroid plexus tumor was diagnosed at midtrimester anomaly scan. Since it was difficult to rule out a malignant tumor, pregnancy was terminated. However, MRI, autopsy, and histopathology confirmed a choroid plexus papilloma, which is known to have good prognosis. In case three, prenatal MRI showed features of neurological involvement in tuberous sclerosis. However child has no neurological manifestations at 1 year of age. Hence, prognostication of prenatally diagnosed brain tumors remains a challenge.How to cite this articleVasudeva A, Amin SV, Kadavigere R, Girisha KM, Rai L. Prenatal Diagnosis of Intracranial Tumors and the Difficulties in Prognostication: A Report of Three Cases. Int J Infertil Fetal Med 2015;6(2):88-91.

Cardiac Involvement in Tuberous Sclerosis

Cardiac Involvement in Tuberous Sclerosis

Tratamento dos angiofibromas múltiplos da face com radiofrequência

Tuberous sclerosis is a rare genetic disease with autosomal dominant inheritance, associated with multiple hamartomas in several organs, such as the brain, skin, lung, kidney, heart and eyes. The authors of this study report a case of a 30 years old female patient with tuberous sclerosis, presenting multiple angiofibromas on face treated with high frequency equipment (radiofrequency), and discuss the therapeutic options for treatment of individuals with extensive cutaneous involvement in tuberous sclerosis.

Systems biology of the autophagy-lysosomal pathway

The mechanisms of the control and activity of the autophagy-lysosomal protein degradation machinery are emerging as an important theme for neurodevelopment and neurodegeneration. However, the underlying regulatory and functional networks of known genes controlling autophagy and lysosomal function and their role in disease are relatively unexplored. We performed a systems biology-based integrative computational analysis to study the interactions between molecular components and to develop models for regulation and function of genes involved in autophagy and lysosomal function. Specifically, we analyzed transcriptional and microRNA-based post-transcriptional regulation of these genes and performed functional enrichment analyses to understand their involvement in nervous system-related diseases and phenotypes. Transcriptional regulatory network analysis showed that binding sites for transcription factors, SREBP1, USF, AP-1 and NFE2, are common among autophagy and lysosomal genes. MicroRNA enrichment analysis revealed miR-130, 98, 124, 204 and 142 as the putative post-transcriptional regulators of the autophagy-lysosomal pathway genes. Pathway enrichment analyses revealed that the mTOR and insulin signaling pathways are important in the regulation of genes involved in autophagy. In addition, we found that glycosaminoglycan and glycosphingolipid pathways also make a major contribution to lysosomal gene regulation. The analysis confirmed the known contribution of the autophagy-lysosomal genes to Alzheimer and Parkinson diseases and also revealed potential involvement in tuberous sclerosis, neuronal ceroidlipofuscinoses, sepsis and lung, liver and prostatic neoplasms. To further probe the impact of autophagy-lysosomal gene deficits on neurologically-linked phenotypes, we also mined the mouse knockout phenotype data for the autophagylysosomal genes and found them to be highly predictive of nervous system dysfunction. Overall this study demonstrates the utility of systems biology-based approaches for understanding the autophagy-lysosomal pathways and gaining additional insights into the potential impact of defects in these complex biological processes.

Vascular involvement in tuberous sclerosis

Vascular involvement in tuberous sclerosis (TS) is rare. Central and peripheral aneurysms and large and medium size arterial stenotic-occlusive disease have been reported in patients with TS. We present here three pediatric patients with TS and severe vascular abnormalities, followed by a review of the literature. The three cases include a 14-month-old girl with polycystic kidneys and cerebral tubers who had a large asymptomatic abdominal aortic aneurysm, a 2-year-old boy with multiple features of TS who had hypertension and was found to have mid-aortic syndrome with bilateral renal artery stenosis, and an 18-year-old girl with abdominal pain and TS features who had greater than 70% celiac artery stenosis. In all cases, noninvasive vascular imaging modalities were utilized for either initial diagnosis, surveillance, or both. These cases highlight the collaborative roles of the pediatric nephrologist and cardiovascular imager in the diagnosis and management of the vascular complications in TS patients. Appropriate care can only be made through a high index of suspicion.

Developing multiple lung nodules in a renal transplant recipient with tuberous sclerosis who had undergone bilateral nephrectomy due to renal cell carcinomas

A 38-year-old woman, who had been diagnosed as having tuberous sclerosis (TSC), incidentally presented with asymptomatic multiple pulmonary nodules detected by computed tomography during immunosuppressive therapy for 6 years after renal transplantation. The recurrence of renal cell carcinoma (RCC) was suspected because the patient underwent bilateral nephrectomies due to RCC in dialysis kidneys before transplantation. However, the lung biopsy specimen was diagnosed as multifocal micronodular pneumocyte hyperplasia (MMPH), which is an extremely rare benign lung involvement in TSC. It is necessary to consider MMPH in the differential diagnosis when lung nodules are observed in TSC patients.

Forehead plaque: A cutaneous marker of CNS involvement in tuberous sclerosis

Tuberous sclerosis complex (TSC) is a neurocutaneous genodermatosis characterized by hamartoma formation in multiple organs. There are no definite cutaneous markers suggestive of central nervous system (CNS) involvement in TSC. To study association of forehead plaque seen in tuberous sclerosis patients and CNS involvement in TSC. This is a retrospective study of 15 cases of tuberous sclerosis in varying age groups - from 1.5 to 50 years. All the cases were thoroughly evaluated with detailed history; clinical examination; and relevant investigations like X-rays of chest, skull, hands and feet; ultrasound abdomen and computed tomography of brain. Out of the 15 cases, CNS involvement was seen in 8 cases. Seizures were present in 8 cases (53.33%) and mental retardation was seen in 6 cases (40%). Computerized tomography of brain revealed subependymal nodules (SENs) in eight cases (53.33%). In addition to SENs, subependymal giant cell astrocytomas and cortical tubers were seen in 2 cases each. Out of these 8 cases having CNS involvement, in 7 cases forehead plaque was observed. In 1 case, no forehead plaque was observed (X 2 = 1.07, P < 0.05). This study shows that there is a statistically significant relationship between the presence of a forehead plaque and CNS involvement in TSC. Therefore, forehead plaque may be considered as a novel cutaneous marker to know the CNS involvement in TSC at an early stage.

Tuberous sclerosis — A multi system disease

Tuberous sclerosis is a genetic disease with autosomal dominant inheritance, associated with hamartomas in several organs and various skin findings. A case of a ten year old boy is presented here to highlight the multisystem involvement in tuberous sclerosis. The child had seizures, facial papular naevi and peri-ungual fibromas. MRI revealed cortical tubers, white matter lesions and subependymal nodules. Orbital ultrasound showed retinal hamartoma on the left side. Ultrasound of the abdomen revealed a soft tissue mass at the upper pole of left kidney with a small cyst in right kidney.

Bilateral renal angiomyolipoma coexistent with pulmonary lymphangioleiomyomatosis and tuberous sclerosis

A case of bilateral renal angiomyolipoma coexistent with pulmonary lymphangioleiomyomatosis and tuberous sclerosis was described, being in shock with massive hematuria. The left giant angiomyolipoma, filling the almost entire abdomen, was complicated with two large hump and moniliform aneurysms. This life-threatening hemorrhage was successfully treated by transcatheter arterial embolization; packing mechanically detachable coils into the aneurysms and embolization of trunk of the left renal artery. Lymphangioleiomyomatosis has been suggested to be an incomplete expression of tuberous sclerosis. Although coexisting renal and pulmonary involvement in tuberous sclerosis is rare, it is important to recognize lymphangioleiomyomatosis as a pulmonary involvement of angiomyolipoma with tuberous sclerosis.

LONG-TERM OUTCOME OF TRANSCATHETER EMBOLIZATION OF RENAL ANGIOMYOLIPOMAS DUE TO TUBEROUS SCLEROSIS COMPLEX

Complications from renal angiomyolipomas (AMLs) are common in patients with tuberous sclerosis complex (TSC) and tumors greater than 4 cm are more likely to cause symptoms. AMLs are the most common cause of death in adults with TSC. We present our long-term experience with transcatheter tumor embolization as a definitive treatment for AMLs due to TSC. A total of 16 patients with TSC between 7.5 and 47.2 years old with symptomatic or large (4 to 21 cm) AMLs underwent embolization. Followup consisted of periodic physician visits or telephone contacts and renal imaging. The 16 patients underwent 18 treatment sessions to embolize 27 tumors. There were no intraoperative complications. The post-embolization syndrome occurred in 11 individuals but all responded to medical management. Two individuals had an arterial aneurysm within a tumor. The AML size decreased in the 13 patients who were imaged 3 months after treatment, and the 7 patients who were imaged 3 to 9 years after treatment have shown no tumor regrowth. No renal failure or hemorrhage has developed in patients following embolization. Transcatheter embolization of symptomatic or large AMLs due to TSC prevents hemorrhage and renal loss. The treatment is minimally invasive, preserves renal function, and can be performed multiple times. All of the patients who underwent followup renal imaging after embolization showed decreased AML size, and none of the 16 patients has developed renal loss or renal insufficiency in these individuals. Embolization should be considered the initial treatment of choice for large or symptomatic AMLs.

ISOLATED UNILATERAL TUBEROUS SCLEROSIS-ASSOCIATED RENAL CYSTIC DISEASE IN A NEONATE

We present a male infant with antenatally detected, focal, unilateral apparently isolated renal cystic disease with morphological features of renal involvement in tuberous sclerosis. Only one previous case with similar presentation has been described. Most affected children present with either diffuse bilateral renal cystic disease or extrarenal manifestations. The major genes involved in tuberous sclerosis are now well described, and early onset of severe renal cystic disease in affected children often is related to the presence of a contiguous gene deletion syndrome involving TSC2 and PKD1 on chromosome 16.

Pulmonary involvement in tuberous sclerosis

Tuberous sclerosis is a neurocutaneous syndrome involving many tissues. Pulmonary involvement is rare. Pulmonary cases are usually women of child-bearing age who present with spontaneous pneumothorax or progressive dyspnea. In childhood and, even more, in male patients, pulmonary involvement by tuberous sclerosis is exceptional. We report on a 4-year-old male patient diagnosed in the first months of life with tuberous sclerosis with predominantly respiratory symptoms (frequently with acute RDS criteria), in whom lung involvement was pathologically confirmed.

Pathogenesis of multifocal micronodular pneumocyte hyperplasia and lymphangioleiomyomatosis in tuberous sclerosis and association with tuberous sclerosis genes TSC1 and TSC2.

Tuberous sclerosis (TSC) is a rare, genetically determined disorder / familial tumor syndrome, currently diagnosed using specific clinical criteria proposed by Gomez, including the presence of multiorgan hamartomas. Pulmonary involvement in TSC is well known as pulmonary lymphangioleiomyomatosis (LAM), which has an incidence of 1-2.3% in TSC patients. LAM has immunohistochemical expression of both smooth-muscle actin and a monoclonal antibody specific for human melanoma, HMB-45. It has recently been reported that multifocal micronodular pneumocyte hyperplasia (MMPH) associated with TSC should be considered as a distinct type of lung lesion, whether it occurs with or without LAM. Two predisposing genes have been found in families affected by TSC; approximately half of the families show linkage to TSC1 at 9q34.3, and the other half show linkage to TSC2 at 16p13.3. TSC genes are considered to be tumor suppressor genes, and mutations in them may lead to abnormal differentiation and proliferation of cells. Tuberin, the TSC2 gene product, has recently been found to be expressed in LAM and MMPH. In this article we discuss the histogenesis and genetic abnormalities of neoplastic lesions associated with TSC, and we review the current understanding of the pathogenesis of pulmonary hamartomatous lesions such as LAM and MMPH in TSC.

Cerebellar involvement in tuberous sclerosis

Cerebellar involvement in tuberous sclerosis is apparently less than cerebral involvement. In this article, we report CT and MR imaging findings in four tuberous sclerosis patients with apparent cerebellar changes. In one patient with extensive follal calcifications, hypoplasia of the superior vermis, and agenesis of the inferior vermis were associated findings, and clinical correspondence was evident, consisting of a decreased ability to coordinate movements.

Multiple organ involvement in tuberous sclerosis

Tuberous sclerosis is an uncommon heredito-familial disease. A rare case of multiple organ involvement is reported.

A cross sectional study of renal involvement in tuberous sclerosis.

Renal disease is a frequent manifestation of tuberous sclerosis (TSC) and yet little is known about its true prevalence or natural history. We reviewed the notes of 139 people with TSC, who had presented without renal symptoms, but who had been investigated by renal ultrasound. Information on the frequency, type, and symptomatology of renal involvement was retrieved. The prevalence of renal involvement was 61%. Angiomyolipomas were detected in 49%, renal cysts in 32%, and renal carcinoma in 2.2%. The prevalence of angiomyolipoma was positively correlated with age, compatible with a two hit aetiology. Renal cysts were the commoner lesion in young children, and their prevalence did not appear to be age related. Renal investigation in people with TSC had been inconsistent and limited. We suggest guidelines for renal investigation in those with TSC.

Pulmonary Tuberous Sclerosis

We describe the clinical presentation, pulmonary function tests, chest radiograph, and computed tomography findings, response to hormonal treatment, and duration of survival of nine patients with pulmonary involvement in tuberous sclerosis complex with follow-up over an average of 17 years (range, 1 to 35 years) since diagnosis. All patients were female, and the average age at onset of symptoms was 16 years (range, 3 months to 39 years); pulmonary symptoms did not develop until an average age of 33 years (range, 22 to 46 years). There was an average delay of 8 years before the correct diagnosis was made. The most common presenting clinical features were seizures, pneumothorax, bleeding into a renal angiomyolipoma, dyspnea, and typical skin changes. Pulmonary function tests commonly demonstrated obstruction to airflow and reduced single-breath diffusing capacity. Chest radiograph and computed tomography characteristically demonstrated diffuse interstitial infiltrates with cystic changes. Two asymptomatic patients with mild pulmonary involvement have remained in stable condition without hormonal therapy. The remaining seven patients had moderate to severe airflow obstruction; of these, five underwent hormonal therapy. Three patients had a clinical response to treatment. Two patients who did not receive hormonal treatment died of progressive respiratory failure. Most patients with pulmonary involvement in tuberous sclerosis have a slowly declining clinical course. Although the available data are limited, they suggest that a trial of hormonal therapy is recommended both for symptomatic patients and for those with declining pulmonary function. Tuberous sclerosis complex should be suspected in all patients with the diagnosis of lymphangioleiomyomatosis.