Tuberous sclerosis complex: Recent advances in manifestations and therapy

Tuberous sclerosis complex is an autosomal dominant inherited disorder characterized by generalized involvement and variable manifestations with a birth incidence of 1:6000. In a quarter of a century, significant progress in tuberous sclerosis complex has been made. Two responsible genes, TSC1 and TSC2, which encode hamartin and tuberin, respectively, were discovered in the 1990s, and their functions were elucidated in the 2000s. Hamartin–Tuberin complex is involved in the phosphoinositide 3‐kinase–protein kinase B–mammalian target of rapamycin signal transduction pathway, and suppresses mammalian target of rapamycin complex 1 activity, which is a center for various functions. Constitutive activation of mammalian target of rapamycin complex 1 causes variable manifestations in tuberous sclerosis complex. Recently, genetic tests were launched to diagnose tuberous sclerosis complex, and mammalian target of rapamycin complex 1 inhibitors are being used to treat tuberous sclerosis complex patients. As a result of these advances, new diagnostic criteria have been established and an indispensable new treatment method; that is, “a cross‐sectional medical examination system,” a system to involve many experts for tuberous sclerosis complex diagnosis and treatments, was also created. Simultaneously, the frequency of genetic tests and advances in diagnostic technology have resulted in new views on symptoms. The numbers of tuberous sclerosis complex patients without neural symptoms are increasing, and for these patients, renal manifestations and pulmonary lymphangioleiomyomatosis have become important manifestations. New concepts of tuberous sclerosis complex‐associated neuropsychiatric disorders or perivascular epithelioid cell tumors are being created. The present review contains a summary of recent advances, significant manifestations and therapy in tuberous sclerosis complex.     

Bilateral Chromophobe Cell Renal Carcinoma in Tuberous Sclerosis Comple

We report on a patient with tuberous sclerosis complex and polycystic kidney disease who developed bilateral chromophobe cell renal carcinoma. We discuss the tuberous sclerosis complex, associated bilateral renal cell carcinoma, polycystic kidney disease and chromophobe cell renal carcinoma; a recently established subtype with a rather favorable prognosis.
In a patient with tuberous sclerosis complex and multiple space-occupying lesions, a diagnosis of angiomyolipoma should be considered first but bilateral and/or multifocal renal cell carcinoma is a likely diagnosis.     

RENAL LESION GROWTH IN CHILDREN WITH TUBEROUS SCLEROSIS COMPLEX

Purpose

Renal lesions, including angiomyolipoma, renal cysts (simple and polycystic kidney disease) and renal cell carcinoma, develop in patients with tuberous sclerosis complex. While there is limited information that these lesions may grow in adults with tuberous sclerosis complex, the incidence, characterization and growth rate in children have not been reported. Also, the age at which these lesions first appear, thus providing insight into their natural history, is unknown. We present our data from a longitudinal renal surveillance study of children with tuberous sclerosis complex.

Materials and Methods

Since 1985 children with tuberous sclerosis complex at our hospital have undergone periodic renal imaging by ultrasonography or computerized tomography to monitor renal lesions. A total of 35 girls and 25 boys 1 to 18 years old have undergone at least 2 or more annual renal ultrasounds.

Results

On initial evaluation 33 of 60 children (55%) (mean age 6.9 years) had an identifiable renal lesion, which increased to 48 of 60 (80%) at followup (mean age 10.5 years). Angiomyolipoma was the most frequent lesion (75%) followed by simple renal cysts (17%). Angiomyolipomas increased in size and/or number in 10 of 18 boys (56%) and 18 of 27 girls (66%). The largest growth rate in 1 year was from 0 to 4 cm. and from 5 to 9 cm. in diameter. The youngest patient demonstrated lesions at age 2 years. The average age at which a normal ultrasound became abnormal was 7.2 years. While a total of 27 patients had a normal ultrasound on entering the study, lesions had developed in 15 at followup (11 with angiomyolipomas, 4 with cysts). Five patients had cysts that had disappeared at followup. A 7-year-old boy had a 9 cm. renal cell carcinoma removed. One patient has renal lesions characteristic of autosomal dominant polycystic kidney disease.

Conclusions

Renal involvement in patients with tuberous sclerosis complex begins in infancy, and angiomyolipoma is the most common lesion (75%). Angiomyolipomas are more likely to grow than remain stable, although the rate of growth varies. Simple renal cysts may appear or disappear with time but angiomyolipomas do not disappear. An initially normal renal ultrasound does not rule out future development of lesions. Periodic surveillance is indicated in children with tuberous sclerosis complex.     

Nephrotic syndrome and rapid renal failure in autosomal dominant polycystic kidney disease

A 44-year-old man, with autosomal dominant polycystic kidney disease and hypertension under satisfactory control, developed nephrotic syndrome with negative serology. Open renal biopsy revealed focal glomerular sclerosis. Prior to the appearance of heavy proteinuria, serum creatinine was 1.7 mg/dl. After the nephrotic syndrome had been established, renal function deteriorated rapidly and hemodialysis was started within 2.6 years. In patients with autosomal dominant polycystic kidney disease, the appearance of nephrotic range proteinuria along with a rapid decline in renal function indicates the presence of a glomerular lesion, which needs to be investigated by renal biopsy.     

A case of angiomyolipoma originating from polycystic kidney with horseshoe kidney

A case of renal angiomyolipoma originating from polycystic kidney with horseshoe kidney is reported. A 32-year-old woman visited our hospital with the complaint of proteinuria. with computerized tomographic scan and further examinations the patient was diagnosed as having renal angiomyolipoma with tuberous sclerosis. The tumor originated from a polycystic horseshoe kidney. Three weeks later, she complained of right flank pain and was diagnosed with spontaneous rupture of the angiomyolipoma. Right heminephrectomy was performed and histological examination confirmed the preoperative diagnosis. Some discussion is made on the characteristics and treatment of renal angiomyolipoma, and the statistics on renal diseases with tuberous sclerosis in Japan are presented.     

Tuberous sclerosis and polycystic kidney disease in a 3-month-old infant

Tuberous sclerosis (TSC) is an autosomal dominantly inherited multisystemic disease characterized by the development of hamartomas predominantly in brain and kidneys. The TSC2 gene for tuberous sclerosis is localized on chromosome 16p13.3 immediately adjacent to PKD1, the gene for autosomal dominant polycystic kidney disease (ADPKD). A TSC2-PKD1 contiguous gene syndrome caused by chromosomal microdeletions disrupting both the TSC2 and PKD1 genes has been identified in patients with TSC and early-onset severe ADPKD. We report a 3-month-old Caucasian girl of non-consanguineous parents with TSC and early manifestation of ADPKD. She presented with right-sided focal seizures, two small hypopigmented areas on the left flank, and elevated blood pressure requiring antihypertensive treatment. Brain magnetic resonance imaging revealed typical signs of tuberous sclerosis and abdominal ultrasonography showed bilaterally enlarged kidneys with multiple cysts resembling those seen in ADPKD. There was no family history of renal disease or of tuberous sclerosis. Findings were highly suspicious of TSC2-PKD1 contiguous gene syndrome. Using fluorescence in situ hybridization and plasmid probe CW23, which spans the adjacent 3 regions of TSC2 and PKD1 genes, we identified a submicroscopic deletion on only one of the chromosomes 16p13.3, thus permitting the diagnosis of the TSC2-PKD1 contiguous gene syndrome.     

Renal cystic disease in the tuberous sclerosis complex

Renal cysts are relatively common in tuberous sclerosis, occasionally causing severe cystic disease with renal failure. Although the imaging features and gross appearances resemble dominant polycystic kidney disease, the histopathological appearances are distinctive, perhaps unique, differing from appearances in other forms of renal cystic disease. The cysts are lined with hypertrophic and hyperplastic cells that probably cause the cysts by obstructing lumina. The renal abnormality may be inherent in tuberous sclerosis, although inconstantly expressed. Renal enlargement is sometimes the first recognized expression of tuberous sclerosis, and the occurrence of renal cysts in a child with seizures and developmental retardation leads to a strong suspicion of the diagnosis.Presented at the Festschrift for Professor R. H. R. White on March 6, 1992, Birmingham, UK     

Changes in Health-Related Quality of Life (HRQOL) of a Specific Group of Adolescent Idiopathic Scoliosis (AIS) Patients Who Came Across Both Bracing and Surgery

Background/Purpose of the StudyChanges in health-related quality of life (HRQOL) of AIS patients coming across both bracing and surgery have not yet reported. These patients received two major clinical interventions and their HRQOL might be different from previous articles. The aim of this study is to evaluate the changes of HRQOL of a specific group of AIS patients who experienced both bracing and surgery.MethodsOne hundred and twenty-eight patients requiring surgery with prior bracing treatment were identified from the electronic record. SRS-22 questionnaire was completed at 7 time points crossing both interventions (namely “Before”, “Bracing ≤ 1 year”, “Bracing > 1 year”, “Pre-op”, “Post-op”, “Post-op ≤ 1 year, and “Post-op 1-2 years”).ResultsSRS-22 “Function”, “Pain” and “Self-image” scores were decreased from “Before” to “Bracing ≤ 1 year” when started bracing and raised at “Bracing > 1 year”. The 3 scores were dropped from “Bracing > 1 year” to “Pre-op”, particularly on “Self-image”. “Function” and “Pain” were significantly dropped from “Pre-op” to “Post-op” and kept raising until “Post-op 1–2 years”. “Self-image” was improving after “Pre-op”. “Mental” was relatively stable along the timeline.ConclusionThis study described the changes in HRQOL of a specific group of AIS patients. Scores were dropped after the two major clinical interventions and recovered afterwards. Medical professionals were able to plan and provide appropriate supports on the expected changes in HRQOL, especially on function, pain and mental.     

A novel genomic model for predicting the likelihood of delayed graft function in DCD kidney transplantation

BackgroundThe high incidence of delayed graft function (DGF) following kidney transplantation with donation after cardiac death allografts (DCD-KT) poses great challenges to transplant clinicians. This study aimed to explore the DGF-related biomarkers and establish a genomic model for DGF prediction specific to DCD KT.MethodsBy data mining a public dataset ({"type":"entrez-geo","attrs":{"text":"GSE43974","term_id":"43974"}}GSE43974), the key DGF-related genes in DCD kidney biopsies taken after short-time reperfusion (45–60 min) were identified by differential expression analysis and a LASSO-penalized logistic regression model. Their coefficients for modeling were calculated by multivariate logistic regression. Receiver operating characteristic curves and a nomogram were generated to evaluate its predictive ability for DGF occurrence. Gene set enrichment analysis (GSEA) was performed to explore biological pathways underlying DGF in DCD KT.ResultsFive key DGF-related genes (CHST3, GOLPH3, ZBED5, AKR1C4, and ERRFI1) were first identified, all of which displayed good discrimination for DGF occurrence after DCD KT (all P<0.05). A five-mRNA-based risk score was further established and showed excellent predictive ability (AUC =0.9708, P<0.0001), which was obviously higher than that of the five genes alone. Eight DGF-related biological pathways in DCD kidneys, such as “arachidonic acid metabolism”, “lysosome”, “proximal tubule bicarbonate reclamation”, “glutathione metabolism”, were identified by GSEA (all P<0.05). Moreover, a convenient and visual nomogram based on the genomic risk score was also constructed and displayed high accuracy for DGF prediction specific to DCD KT.ConclusionsThe novel genomic model may effectively predict the likelihood of DGF immediately after DCD KT or even prior to transplantation in the context of normothermic machine perfusion in the future.     

Autosomal dominant polycystic kidney disease: an unusual presentation as unilateral renal mass in the infant

The onset of autosomal dominant polycystic kidney disease in infants and children is unusual, and renal involvement is typically bilateral. The presentation of a unilateral renal mass in such a disorder is extremely rare. We report a 2-month-old infant with autosomal dominant polycystic kidney disease presenting with unilateral renal involvement; the literature concerning this entity is reviewed.     

Spinal cord involvement in Lewy body-related α-synucleinopathies

Context: Lewy body (LB)-related α-synucleinopathy (LBAS) is the neuropathological hallmark of several neurodegenerative diseases such as Parkinson disease (PD), but it is also found in neurologically asymptomatic subjects. An abnormal accumulation of α-synuclein has been reported also in the spinal cord, but extent and significance of the spinal cord involvement are still poorly defined.Objective: We aimed to review the studies addressing the spinal cord involvement of LBAS in healthy subjects and in patients with PD or other neurodegenerative diseases.Methods: A MEDLINE search was performed using following terms: “spinal cord”, “ α-synucleinopathy”, “α-synuclein”, “Lewy body”, “Parkinson’s disease”, “multiple system atrophy”, “neurodegenerative disorder”.Results: LBAS in the spinal cord is associated with that of the medullary reticular formation and locus ceruleus in the brainstem but not with that in the olfactory bulb and amygdala. The intermediolateral columns of the thoracic and sacral cord are the most frequently and severely affected region of the spinal cord. LBAS occurs in centrally projecting spinal cord neurons integrating pain, in particular from lower body periphery. It also involves the sacral parasympathetic nucleus innervating the smooth muscles of the bladder and distal colon and the Onuf’s nucleus innervating the striated sphincters. The spinal cord lesions may thus play a crucial role in the genesis of frequent non-motor symptoms such as pain, urinary symptoms, bowel dysfunction, autonomic failure including orthostatic hypotension and sexual disturbances. Moreover, these may also contribute to the motor symptoms, since α-synuclein inclusions have been observed in the pyramidal tracts of patients with PD and multiple system atrophy.Conclusion: Recognition of this peculiar spinal cord pathology may help in the management of the related symptoms in subjects affected by α-synucleinopathies.     

Human cystic kidney diseases: epithelial hyperplasia in the pathogenesis of cysts and tumors

Several examples of human renal cystic disease are associated with tubular epithelial hyperplasia. Micropapillary hyperplasia occurs in autosomal dominant polycystic kidney disease, in localized cystic disease, and in acquired cystic disease; neoplastic or severely dysplastic epithelial hyperplasia occurs in von Hippel-Lindau disease; a histopathologically distinctive epithelial hyperplasia occurs in tuberous sclerosis. In all of these conditions the epithelial hyperplasia appears to be responsible for cyst formation by causing tubular or ductal luminal obstruction, and in all of these conditions, save localized cystic disease (a rare condition with very few reported cases), epithelial hyperplasia imposes an increased risk of malignancy. The risk seems to be highest in patients under treatment with long-term hemodialysis for end-stage kidney disease. Some of these diseases may share common features, but it appears likely that the histopathological differences reflect different features converging on a common result.     

Anomalous origin of coronary artery: taxonomy and clinical implication

Objective

Anomalous origin of coronary artery is uncommon. The taxonomies of anomalous origin of coronary artery are inconsistent and complex. Conceptual and therapeutic debates remain. The aim of the present study is to reappraise the concept of anomalous origin of coronary artery and to discuss the potential hazards and treatment rationale of this anomaly on basis of literature review.

Methods

A comprehensive literature review was made in terms of the taxonomies including “simple”, “multiple” and “complex” types of anomalous origin of coronary artery.

Results

Anomalous origin of coronary artery can be simply categorized according to the ectopically originated coronary artery. There are a couple of complex anatomical variants: “multiple” type, involving more than one coronary artery or branch, which can be subdivided into 2 subtypes, A) more than one coronary arteries or branches arising from one place; and B) two coronary arteries/branches arising from separate ectopic sites; and “complex” type, associated with acquired heart disease, or congenital heart defects.

Conclusion

Sudden cardiac death in anomalous origin of coronary artery is associated with the anatomical features including abnormal coursing, acute angle take-off and ostial abnormalities. Atherosclerosis is prone to be in the right-sided ectopic and retroaortic coursing coronary artery. Surgical treatment is a definitive therapy. Simple coronary artery bypass grafting is not recommended due to the potential hazards of coronary steal phenomenon and poor patency of mammary arterial grafts, and modified maneuvers such as coronary ostial reimplantation, impinged coronary segment unroofing and coronary stent deployment are advocated instead.     

Autosomal dominant polycystic kidney disease with congenital absence of contralateral kidney

Autosomal dominant polycystic kidney disease is the most frequent hereditary kidney disorder, accounting for 8–10% of the cases of end-stage renal disease. It is characterized by bilateral multiple renal cysts, nevertheless, asymmetric enlargement of the kidneys is frequently observed, and this can lead to diagnostic confusion. We report the rare occurrence of autosomal dominant polycystic disease confined to a right kidney and congenital absence of the contralateral one. Unexpected early onset of terminal renal failure in this hypertensive 23-year-old male is discussed with the review of the literature.     

Sexual function after anterior urethroplasty: a systematic review

BackgroundUrethral surgery outcomes are often evaluated by assessing urinary flow and urethral patency. However, sexual consequences may appear after urethroplasty, impairing quality of life and patient’s perception of success.The aim of this study is to assess the relationship between anterior urethral reconstruction and postoperative sexual dysfunction, including the proposed factors predicting sexual outcomes.MethodsWe searched in PubMed database using the terms: “anterior urethroplasty”, bulbar urethroplasty” or “penile urethroplasty”, and “sexual dysfunction”, “erectile function” or “ejaculation”. Articles were independently evaluated for inclusion based on predetermined criteria. Systematic data extraction was followed by a comprehensive summary of evidence.ResultsThirty-eight studies were included for final analysis. No randomised trial on the topic was found. Urethral surgery might affect different aspects of sexual function: erectile function, ejaculatory function, penile shape and length, and genital sensitivity, leading to severe sexual dysfunction. Patient perception of sexual impairment was related to post-operative satisfaction.ConclusionsSexual dysfunction after anterior urethral reconstruction is an important issue that must be appropriately discussed during preoperative patient counselling. Reported outcomes after anterior urethroplasty should include sexual consequences and relevance, evaluated using validated tools.     

Tuberous sclerosis and the kidney: from mesenchyme to epithelium, and beyond

The renal manifestations of tuberous sclerosis complex (TSC) are remarkably diverse, including polycystic kidney disease, oncocytomas, renal cell carcinomas, and both benign and malignant angiomyolipomas. All of these occur in children as well as adults with TSC. Benign angiomyolipomas, which can cause spontaneous life-threatening hemorrhage, are by far the most prevalent and the greatest source of morbidity. What is particularly unusual about TSC, setting it apart from virtually all other inherited forms of renal disease, is the abnormalities of both mesenchymal cells (angiomyolipomas) and epithelial cells (cysts, oncocytomas, and carcinomas). Recently, the TSC1/TSC2 protein complex was shown to inhibit the kinase mTOR (mammalian target of rapamycin). This places TSC1/TSC2 at center stage in signaling pathways that regulate cell growth. Furthermore, recent advances in TSC1/TSC2 signaling open the door for targeted therapy for TSC patients. Here, we will address the genetic, cellular and biochemical mechanisms that may contribute to the unusually broad spectrum of renal disease in cells with TSC1 or TSC2 mutations, and consider how the TSC signaling pathways may be linked to other renal diseases such as polycystic kidney disease and renal cell carcinoma.     

Radiation therapy for nonmetastatic medically inoperable upper-tract urothelial carcinoma

BackgroundThe standard management for upper urinary tract urothelial carcinoma (UTUC) is radical nephroureterectomy (RNU). However, some patients cannot undergo this procedure for several reasons, such as unresectable disease, old age, and multiple comorbidities. Our study explored the potential safety and effectiveness of radiotherapy as a curative treatment for UTUC patients unfit for surgery.MethodsThe data of patients treated with radiotherapy between December 2017 and November 2019 were retrospectively reviewed. For the literature review, computerized PubMed Medline, Index Medicus, and Web of Science databases and reference lists from the identified publications of interest were used. And “upper-tract urothelial carcinoma” and “radiotherapy” were used as key words in the search.ResultsWe describe 8 patients with UTUC who were treated with radiotherapy. The median follow-up time was 13.5 months (range, 8.6–30.9 months). Local tumor control was achieved in all patients. However, distant metastases were observed in 2 patients with T3-4/N+ status. One patient had T4 status and the other had N2+ status. The patients died of tumor progression at 15.0 and 17.7 months. In addition, the other 6 patients who were still alive had relatively early-stage tumors without nodal involvement. Regarding acute toxicity, according to the CTCAE v5.0, mild side effects were noted, including grade 1 nausea and diarrhea. Four patients developed mild anemia, generally of grade 1–2. One patient experienced grade 3 anemia, but it was manageable and improved with symptomatic support. In addition, no grade 4 acute or late toxicities were observed. No significant long-term impairment of renal function occurred.ConclusionsFor patients with nonmetastatic UTUC who are not suitable for surgery, radiotherapy is a safe treatment and can achieve good local tumor control.     

The influence of prostatic calculi on lower urinary tract symptoms and sexual dysfunction: a narrative review

Prostatic calculi (PC) are commonly found in patients who present for urologic consultation. However, the effect of PC on urinary symptoms remains controversial. In this study, we searched the Embase and PubMed databases for literature related to the following keywords: “prostatic calculi”, “prostatic stone”, “prostatic lithiasis” and “prostatic calcification”, along with the limits, “lower urinary tract symptoms”, “sexual dysfunction”, “erectile dysfunction”, “erectile function”, and “premature ejaculation”. According to the literature, there are various subtypes of PC based on X-ray or ultrasound findings, including type I/II, type A/B, and endogenous PC/extrinsic PC. Furthermore, the formation of PC remains unclear, and more importantly, the ability of PC to cause lower urinary tract symptoms (LUTS) and sexual dysfunction (SD) is worth exploring. We retrospectively reviewed all available literature and found that most studies agreed that PC are associated with LUTS. The factors which may play an important role in the pathogenesis of LUTS include the size and location of PC, induced inflammation, and the blood flow of the prostate. Similarly, SD was also examined in the patients with PC, and psychological factors cannot be ignored in this regard. However, more in-depth study of the molecular mechanisms, including prospective, controlled, longitudinal, and large- sample studies, are needed in the future.     

Reins kystiques de l’enfant

Thanks to prenatal ultrasound scan, cystic kidneys, as well as obstructive uropathies, are the most frequent renal anomalies identified during pregnancy. They should be recognized because of genetic and clinical implications. The most frequent are autosomal dominant and recessive polycystic kidney diseases, followed by renal developmental anomalies linked to TCF2 gene. Renal cysts are also observed in other hereditary diseases or multiple malformation syndromes (tuberosis sclerosis, Meckel-Grubber syndrome, Oro-facial digital type 1 syndrome…). The diagnosis is based on a sonographic and morphological analysis of renal abnormalities, on the search for family histories and extra-renal manifestations. A better classification of these patients allows tailor-made follow-up and care improvement.     

Clinical and pathological features of renal epithelioid angiomyolipoma (PEComa): A single institution series

Renal angiomyolipomas are benign tumors of the kidney that belong to the ‘PEComa: perivascular epithelioid cell’ family. Epithelioid AMLs (eAML) are a rare monotypic subtype with malignant potential, that can occur sporadically or be associated with tuberous sclerosis (TSC). Due to their epithelioid nature, eAMLs can closely resemble high-grade renal cell carcinoma (RCC), which may result in misdiagnosis. Multiple clinicopathologic parameters are predictive of worse outcomes for patients with eAML. Those can be used to stratify patients into groups with low, intermediate and high risk for disease progression. A high index of suspicion and a thorough immunohistochemical study are required to correctly diagnose eAML. Radiographically, eAMLs are also a diagnostic challenge as they share features with RCC on CT and MR imaging. Due to this close mimicry, the true incidence of eAML is thought to be much higher than 200 cases as reported in the literature. We report a series of four patients diagnosed with eAML and compare their clinical courses. We also report on the successful treatment of a patient with pulmonary metastasis from eAML using the mTOR inhibitor, everolimus. By identifying eAML and recognizing its high-risk features, it is possible mTOR inhibitors may have a meaningful role in the adjuvant treatment of these patients.