Tuberous sclerosis complex combined with primary lymphedema:A case report

BACKGROUND Tuberous sclerosis complex(TSC)and primary lymphedema(PLE)are both rare diseases,and it is even rarer for both to occur in the same patient.In this work,we have provided a detailed description of a patient's clinical presentation,imaging findings,and treatment.And a retrospective analysis was conducted on 14 published relevant case reports.CASE SUMMARY A 16-year-old male came to our hospital for treatment due to right lower limb swelling.This swelling is already present from birth.The patient’s memory had been progressively declining.Seizures had occurred 1 year prior at an unknown frequency.The patient was diagnosed with TSC combined with PLE through multimodal imaging examination:Computed tomography,magnetic resonance imaging,and lymphoscintigraphy.The patient underwent liposuction.The swelling of the patient's right lower limb significantly improved after surgery.Epilepsy did not occur.after taking antiepileptic drugs and sirolimus.CONCLUSION TSC with PLE is a rare and systemic disease.Imaging can detect lesions of this disease,which are important for diagnosis and treatment.

Tuberous Sclerosis Complex:Imaging Characteristics in 11 Cases and Review of the Literature

Tuberous sclerosis complex（TSC） is an uncommon multiorgan disorder that may present many and different manifestations on imaging. Radiology plays an important role in diagnosis and management, and can substantially improve the clinical outcome of TSC. Therefore, a comprehensive understanding of this disease is essential for the radiologist. The manifestations of TSC on computer tomography（CT） and magnetic resonance（MR） images were analyzed. Eleven patients with a clinical diagnosis of TSC were retrospectively reviewed. Central nervous system lesions included subependymal nodules（SENs）（11/11）, subependymal giant cell astrocytomas（SEGAs）（2/11）, cortical and subcortical tuber lesions（5/11）, and white matter lesions（4/11）. Of the 6 patients with abdominal scans, there were 6 cases of renal angiomyolipomas（AMLs）, and one case of hepatic AMLs. Of the 4 patients undergoing chest CT, lung lymhangioleiomyomatosis（LAM）（2/4）, and multiple small sclerotic bone lesions（2/4） were observed. Different modalities show different sensitivity to the lesion. Analysis of images should be integrated with patients＇ history in order to diagnose TSC.

Tuberous sclerosis complex presenting as primary intestinal lymphangiectasia: A case report

BACKGROUND Primary intestinal lymphangiectasia(PIL)is a rare congenital protein-losing enteropathy caused by dysplasia of the small intestinal lymphatics.The cause of the disease is unknown.Through a literature review,we found that PIL and tuberous sclerosis complex(TSC)have some common symptoms and molecular pathways.CASE SUMMARY Here,we present the case of a patient with a three-year history of primary intestinal lymphangiectasia.The patient most recently visited the hospital with abdominal distension and swelling of the left leg.His mother told us that she was diagnosed with TSC one year previously,which alerted us because the patient had multiple regions of pigmentation.To evaluate the condition of the child and make a definite diagnosis,multiple imaging examinations were performed,as was TSC gene analysis.The results met the diagnostic criteria for TSC.The patient was discharged after symptomatic treatment.Through a review of the literature,it can be seen that changes at the molecular gene level of TSC can lead to abnormal lymphatic vessels.CONCLUSION In summary,when patients with hypomelanotic macules or enamel hypoplasia are diagnosed with PIL,TSC gene screening may be important for further diagnosis.

Tuberous sclerosis complex-lymphangioleiomyomatosis involving several visceral organs:A case report

BACKGROUND Lymphangioleiomyomatosis(LAM)is a rare cystic lung disease characterized by the proliferation,metastasis,and infiltration of smooth muscle cells in the lung and other tissues,which can be associated with tuberous sclerosis complex(TSC).The disorder of TSC has a variable expression,and there is great phenotypic variability.CASE SUMMARY A 32-year-old Chinese woman with a history of multiple renal angioleiomyolipoma presented with a productive cough persisting for over 2 wk.Highresolution chest computed tomography revealed interstitial changes,multiple pulmonary bullae,bilateral pulmonary nodules,and multiple fat density areas of the inferior mediastinum.Conventional and contrast ultrasonography revealed multiple high echogenic masses of the liver,kidneys,retroperitoneum,and inferior mediastinum.These masses were diagnosed as angiomyolipomas.Pathology through thoracoscopic lung biopsy confirmed LAM.Furthermore,high-throughput genome sequencing of peripheral blood DNA confirmed the presence of a heterozygous mutation,c.1831C>T(p.Arg611Trp),of the TSC2 gene.The patient was diagnosed with TSC-LAM.CONCLUSION We highlight a rare case of TSC-LAM and the first report of a mediastinum lymphangioleiomyoma associated with TSC-LAM.

Tuberous Sclerosis Complex Associated with Autism Spectrum Features and Bumetanide as a Pharmacological Indication: A Case Report

A wide variety of genetic and non-genetic pathologies share serious psychiatric symptoms, which determine a poor quality of life for patients and their families. To evaluate whether bumetanide, a drug initially developed as a diuretic and currently analyzed for a new indication in patients with severe neuropsychiatric pathologies, could improve the disruptive and self-injurious behaviors secondary to Tuberous Sclerosis Complex (TSC) and characteristic of the autistic spectrum the case of this 6-year-old patient is considered. Following preclinical and clinical evidence of the efficacy of bumetanide in Tuberous Sclerosis and other neurodevelopmental disorders, the drug may alleviate the psychiatric manifestations (TAND) of Tuberous Sclerosis pathology. This would allow avoiding the excessive prescription of antipsychotic drugs indicated to control disruptive behaviors. Methodology: The Administración Nacional de Medicamentos, Alimentos y Tecnología Médica (ANMAT) approval was requested for compassionate use since it is not an approved drug in Argentina for this indication. The patient was evaluated with laboratory tests at T0, T1, T2, T3 and T4, corresponding to the basal moments, of 7 days, 30 days, 60 days and 90 days after starting the medication. Likewise, behavior was evaluated with the Aberrant Behavior Checklist (ABC) at the same times described. CARS was used for autistic characteristics and TAND Checklist for psychiatric disorders, both at the beginning. Bumetanide was administered at 1 mg/day and increased to 1.5 mg/day one month after the first dose. Results: We observed, in this case, the primary endpoint, irritability, showed moderate improvement. On the contrary, hyperactivity, attention, sociability and better connection through gaze experienced and evident improvement. Regarding isolation scales and stereotyped behaviors, an important improvement was found after 3 months of treatment with bumetanide, an antagonist NKCC1, evaluated through the Aberrant Behavior Checklist (ABC). On the other hand, no remarkable adverse effects were observed.

Tuberous sclerosis complex associated renal clear cell carcinoma(a case report and literature review)

Objective To explore the diagnosis and treatment features of tuberous sclerosis complex associated renal cell carcinoma. Methods A 22-year-old boy with a childhood history of epilepsy and mental retardation pres-

Modeling tuberous sclerosis complex with human induced pluripotent stem cells

Background Tuberous sclerosis complex(TSC)is an autosomal dominant genetic disorder with a birth incidence of I:6000 in the United States that is characterized by the growth of non-cancerous tumors in multiple organ systems including the brain,kidneys,lungs,and skin.Importantly,TSCis also associated with signicant neurological manifestations including epilepsy TSC-associated neuropsychiatric disorders,intellectual disabilities,and autism spectrum disorder.Mutations in the TSCI or TSC2 genes are well-established causes of TSC,which lead to TSC1/TSC2 deficiency in organs and hyper-activation of the mammalian target of rapamycin signaling pathway.Animal models have been widely used to study the effect of TSCl/2 genes on the development and function of the brain.Despite considerable progress in understanding the molecular mechanisms underlying TSC in animal models,a human-specific model is urgently needed to investigate the effects of TSCl/2 mutations that are unique to human neurodevelopment.Data sources Literature reviews and research articles were published in PubMed-indexed journals.Results Human-induced pluripotent stem cells(iPSCs),which capture risk alleles that are identical to their donors and have the capacity to differentiate into virtually any cell type in the human body,pave the way for the empirical study of previously inaccessible biological systems such as the developing human brain.Conclusions In this review,we present an overview of the recent progress in modeling TSC with human iPSC models,the existing limitations,and potential directions for future research.

Occult Renal Cell Carcinoma of Eosinophilic Morphology Detected within Renal Angiomyolipoma Mass in a Patient with Tuberous Sclerosis Complex

The kidney is affected in about 80-85% of tuberous sclerosis complex （TSC） patients. Renal manifestations in TSC patients include an increased incidence of epithelial cysts and tumors, such as multiple renal angiomyolipomas （AMLs）, renal cell carcinoma （RCC）, and oncocytoma. The coexistence of RCC and renal AML within same tumor masses, namely collision tumor, is very rare, and about six cases have been reported. Here, we present a case of a young male with TSC and multiple AMLs, containing RCC with eosinophilic morphology.

A Chinese Tuberous Sclerosis Complex Family and a Novel Tuberous Sclerosis Complex-2 Mutation

Tuberous sclerosis complex （TSC） is a relatively common autosomal dominant genetic disorder affecting l/14,000-1/6000 Western populations.The incidence of TSC in Chinese population is still unknown although case reports of Chinese TSC patients were documented. The main clinical features of TSC include seizures,mental retardation,and the development ofhamartomas in multiple organs such as the skin,brain,lung,heart,and kidney.Indeed,the disease virtually manifests in every organ. Two causative genes for TSC,TSC 1 gene on chromosome 9q34 and TSC2 gene on chromosome16p13,have been identified in 1997 and 1993 respectively.Approximately,70% of cases of TSC are de novo mutations. Chinese TSC patients are more likely to have TSC2 missense and frame shift mutations.Here,we record one Chinese TSC family and it is novel frame shift mutation of TSC2.

A Bama miniature pig model of monoallelic TSC1 mutation for human tuberous sclerosis complex

Tuberous sclerosis complex(TSC)is a dominant genetic neurocutaneous syndrome characterized by multiple organ hamartomas.Although rodent models bearing a germline mutation in either TSC1 or TSC2 gene have been generated,they do not develop pathogenic lesions matching those seen in patients with TSC because of the significant differences between mice and humans,highlighting the need for an improved large animal model of TSC.Here,we successfully generate monoallelic TSC1-modified Bama miniature pigs using the CRISPR/Cas9 system along with somatic cell nuclear transfer(SCNT)technology.The expression of phosphorylated target ribosomal protein S6 is significantly enhanced in the piglets,indicating that disruption of a TSC1 allele activate the mechanistic target of rapamycin(mTOR)signaling pathway.Notably,differing from the mouse TSC models reported previously,the TSC1^(+/−)Bama miniature pig developed cardiac rhabdomyoma and subependymal nodules,resembling the major clinical features that occur in patients with TSC.These TSC1^(+/−)Bama miniature pigs could serve as valuable large animal models for further elucidation of the pathogenesis of TSC and the development of therapeutic strategies for TSC disease.

Epilepsy surgery for tuberous sclerosis complex： a case report and literature review

Tuberous sclerosis complex （TSC） is a multisystem genetic disorder with variable phenotypic expression.Epilepsy is the most common neurological complication and up to 80%-90% of the individuals with TSC suffer from epilepsy at some point in their lifetime. Developmental delay, intellectual impairment, autism, behavioral problems, and neuropsychiatric disorders occur commonly in individuals with TSC and may be associated with poorly controlled epilepsy.~ In this paper we reported a case report of TSC, focusing on the patient＇s clinical symptom, surgical aspects and neuropathology through a comprehensive analysis.

Current role of surgery for tuberous sclerosis complex-associated epilepsy

Tuberous sclerosis complex(TSC)is a rare multisystem,autosomal dominant neurocutaneous syndrome in which epilepsy is the most common of several neurological and psychiatric manifestations.Around two thirds of patients develop drug-resistant epilepsy for whom surgical resection of epileptogenic foci is indicated when seizures remain inadequately controlled following trial of two antiseizure medications.The challenge with presurgical and surgical approaches with patients with TSC is overcoming the complexity from the number of tubers and the multiplex epileptogenic network forming the epileptogenic zone.Data suggest that seizure freedom is achieved by 55%-60%of patients,but predictive factors for success have remained elusive,which makes for unconfident selection of surgical candidates.This article presents three different cases as illustrations of the potential challenges faced when assessing the suitability of TSC patients for epilepsy surgery.

Independent temporal lobe epilepsy in patients with tuberous sclerosis complex

Tuberous sclerosis complex(TSC)is a rare disease that involves multiple organs,including the brain;approximately 80%-90%of TSC patients exhibit TSC-associated epilepsy.Independent temporal lobe epilepsy(TLE),TSC-unrelated epilepsy,is particularly rare in patients with TSC.Here,we describe three patients with TSC with independent TLEs that were confirmed by stereo-electroencephalography(EEG),postoperative pathological findings,and seizure outcome at follow-up.The patients were retrospectively enrolled at two centers;their ictal epileptiform discharge onsets were determined using electrode contacts in the hippocampus during stereo-EEG.The three patients underwent anterior temporal lobectomies and remained seizure-free at 1-5 years after surgery.Postoperative pathological examinations confirmed hippocampal sclerosis in all three patients.Furthermore,postoperative intelligence quotient improvement was evident in one patient,while the quality of life was improved in two patients at 12 months after surgery.

Tuberous sclerosis complex complicated with extraventricular cystic giant cell astrocytoma:case report

Tuberous sclerosis complex （TSC） is one of the most commonly identified neurocutaneous disorders with a prevalence of 1/6000 to 1/9000 in general population. In the patients with TSC, 10%-15% have subependymal giant cell astrocytoma （SGCA） .

Giant renal angiomyolipoma with tuberous sclerosis complex

Though rare,angiomyolipomas(AMLs)are the most common mesenchymal tumors of kidney.In general,AMLs can always be associated with two conditions affecting other organ systems:tuberous sclero-sis complex(TSC)and sporadic lymphangioleiomyoma-tosis.This article presents a case of renal AML occurring in a 14-year-old girl with a definite diagnosis of TSC.She had been diagnosed with TSC at the age of three,and a schedule for close observation was disobeyed.At this time,she underwent a series of examinations:physical examina-tion,ultrasonography,angiography,computed tomography(CT),and magnetic resonance imaging(MRI)scans.The physical examination showed adenoma sebaceum in a butterfly paranasal distribution,and a mass was palpated in the left upper quadrant.There were no neurological deficits.Imaging studies(including ultrasonography,angiography,CT,and MRI)of the abdomen showed a large heterogeneous mass arising from the left kidney.Partial nephrectomy was performed.The pathological diagnosis was hemorrhagic renal AML.No recurrence was found in the three-year follow-up.We concluded that schedule of close observation on patients with TSC should be strictly abided by for the high morbidity of AMLs.The specific risks of renal AMLs are spontaneous hemorrhage and rupture.Treatment options for AMLs include conservative and interventional(total/partial nephrectomy,cryoptherapy,and embolization)treatments.

Prenatal Phenotypical Discrepancy in Monozygotic Twins with Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder characterized by the development of hamartomas in the brain, heart, skin, kidney, lung, retina, and so on. One fetus from family 1 had a cardiac rhabdomyoma from 21 weeks and 6 days of gestational age, and developed multiple rhabdomyomas and tubers in the brain at 23 weeks and 5 days. The counter monozygotic twin fetus remained negative throughout the pregnancy according to imaging examination. A nonsense mutation inTSC2 (c.4762C>T, p.Gln1588*) was identified in both twins, but not in the mother. Family 2 was one pair of twin fetuses caused by a microdeletion of exon 30 withinTSC2 inherited from their apparently asymptomatic mother with mosaic status. The larger fetus was identified as having the first cardiac rhabdomyoma from 17 weeks and 4 days of gestational age. The smaller fetus developed multiple rhabdomyomas until 25 weeks and 6 days of gestational age. Both families terminated the pregnancy. Here, we provide intrauterine examples of clinical variability among monozygotic twins suffering from TSC.

Relationship between gene mutation and clinical phenotype in patients with tuberous sclerosis complex

Objective To study the relationship between gene mutation and clinical phenotype in patients with tuberous sclerosis complex(TSC).Methods The clinical data of76 patients with TSC diagnosed in Guangdong 999 Brain Hospital were collected between May 2007 and 2014 and then TSC gene mutation analysis was performed.Genotype-phenotype analyses for all the patients were also carried out.Results Fifty of the 76(66%)patients

Tuberous sclerosis patient with neuroendocrine carcinoma of the esophagogastric junction:A case report

BACKGROUND Tuberous sclerosis complex(TSC)is a rare inherited disease with non-cancerous tumor growths in the skin,brain,kidneys,heart,and lungs.The co-occurrence of neuroendocrine neoplasm(NEN)with TSC is even rarer.There have been few reports on the relationship between TSC and neuroendocrine tumors(NETs),and fewer on the relationship between TSC and neuroendocrine carcinoma(NEC),a subtype of NEN.This is the first reported case of NEC occurring at the esophagogastric junction in a patient with TSC.CASE SUMMARY A 46-year-old woman visiting our hospital for the treatment of TSC was admitted to the emergency department with tarry stools and dizziness.Computed tomography scans revealed thickness of the gastric cardia,multiple metastatic lesions of the liver,and enlarged lymph nodes near the lesser curvature of the stomach.Esophagogastroduodenoscopy revealed a type 3 tumor located from the esophagogastric junction to the fundus,and the pathological diagnosis by biopsy was NEC.The patient was treated with seven courses of cisplatin+irinotecan,followed by eight courses of ramucirumab+nab-paclitaxel,one course of nivolumab,and two courses of S-1+oxaliplatin.Twenty-three months after the first treatment,the patient died because of disease progression and deterioration of the general condition.CONCLUSION This case of NEC occurring in a patient with TSC indicates a difference in the occurrence of NETs and NECs.

Comparison of Color Fundus Photography, Infrared Fundus Photography, and Optical Coherence Tomography in Detecting Retinal Hamartoma in Patients with Tuberous Sclerosis Complex

Background： A sensitive method is required to detect retinal hamartomas in patients with tuberous sclerosis complex （TSC）. The aim of the present study was to compare the color fundus photography, infrared imaging （IFG）, and optical coherence tomography （OCT） in the detection rate of retinal hamartoma in patients with TSC. Methods： This study included 11 patients （22 eyes） with TSC, who underwent color fundus photography, IFG, and spectral-domain OCT to detect retinal hamartomas. TSC1 and TSC2 mutations were tested in eight patients. Results： The mean age of the 11 patients was 8.0 ± 2.1 years. The mean spherical equivalent was -0.55 ±1.42 D by autorefraction with cycloplegia. In 11 patients （22 eyes）, OCT, infrared fundus photography, and color fundus photography revealed 26, 18, and 9 hamartomas, respectively. The predominant hamartoma was type I （55.6%）. All the hamartomas that detected by color fundus photography or IFG can be detected by OCT. Conclusion： Among the methods of color fundus photography, IFG, and OCT, the OCT has higher detection rate for retinal hamartoma in TSC patients; therefore, OCT might be promising for the clinical diagnosis of TSC.

Clinical characteristics and outcomes of patients with hepatic angiomyolipoma:A literature review

First reported in 1976,hepatic angiomyolipoma(HAML)is a rare mesenchymal liver tumor occurring mostly in middle-aged women.Diagnosis of the liver mass is often incidental on abdominal imaging due to the frequent absence of specific symptoms.Nearly 10%of HAMLs are associated with tuberous sclerosis complex.HAML contains variable proportions of blood vessels,smooth muscle cells and adipose tissue,which renders radiological diagnosis hazardous.Cells express positivity for HMB-45 and actin,thus these tumors are integrated into the group of perivascular epithelioid cell tumors.Typically,a HAML appears on magnetic resonance imaging(or computed tomography scan)as a hypervascular solid tumor with fatty areas and with washout,and can easily be misdiagnosed as other liver tumors,particularly hepatocellular carcinoma.The therapeutic strategy is not clearly defined,but surgical resection is indicated for symptomatic patients,for tumors showing an aggressive pattern(i.e.,changes in size on imaging or high proliferation activity and atypical epithelioid pattern on liver biopsy),for large(>5 cm)biopsy-proven HAML,and if doubts remain on imaging or histology.Conservative management may be justified in other conditions,since most cases follow a benign clinical course.In summary,the correct diagnosis of HAML is challenging on imaging and relies mainly on pathological findings.