A tuberous sclerosis potpourri

Gupta N, Henske EP. Pulmonary manifestations in tuberous sclerosis complex. Am J Med Genet C Semin Med Genet. 2018 Jul 28. doi: 10.1002/ajmg.c.31638. [Epub ahead of print]

Abstract

Tuberous sclerosis complex has manifestations in many organ systems, including brain, heart, kidney, skin, and lung. The primary manifestations in the lung are lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyperplasia (MMPH). LAM affects almost exclusively women, and causes cystic lung destruction, pneumothorax, and chylous pleural effusions. LAM can lead to dyspnea, oxygen dependence, and respiratory failure, with more rapid disease progression during the premenopausal years. In contrast, MMPH affects men and women equally, causing small nodular pulmonary deposits of type II pneumocytes that rarely progress to symptomatic disease. Here, we review the clinical features and pathogenesis of LAM and MMPH.

Abstract

Tuberous sclerosis complex has manifestations in many organ systems, including brain, heart, kidney, skin, and lung. The primary manifestations in the lung are lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyperplasia (MMPH). LAM affects almost exclusively women, and causes cystic lung destruction, pneumothorax, and chylous pleural effusions. LAM can lead to dyspnea, oxygen dependence, and respiratory failure, with more rapid disease progression during the premenopausal years. In contrast, MMPH affects men and women equally, causing small nodular pulmonary deposits of type II pneumocytes that rarely progress to symptomatic disease. Here, we review the clinical features and pathogenesis of LAM and MMPH.

Bissler JJ, Budde K, Sauter M, Franz DN, Zonnenberg BA, Frost MD, Belousova E, Berkowitz N, Ridolfi A, Christopher Kingswood J. Effect of everolimus on renal function in patients with tuberous sclerosis complex: evidence from EXIST-1 and EXIST-2. Nephrol Dial Transplant. 2018 Jul 19. doi: 10.1093/ndt/gfy132. [Epub ahead of print]

Abstract

BACKGROUND:

A reduction in renal angiomyolipoma volume observed with everolimus (EVE) treatment in patients with tuberous sclerosis complex (TSC) has been postulated to translate to clinical benefit by reducing the risk of renal hemorrhage and chronic renal failure.

METHODS:

The long-term effects of EVE on renal function (∼4 years of treatment) were examined in patients treated with EVE in the Phase 3 EXIST-1 and EXIST-2 studies. Patients in EXIST-1 had TSC and subependymal giant cell astrocytoma (SEGA), and patients in EXIST-2 had renal angiomyolipoma and a definite diagnosis of TSC or sporadic lymphangioleiomyomatosis. EVE was administered at 4.5 mg/m2/day, with adjustment to achieve target trough levels of 5-15 ng/mL in EXIST-1 and at 10 mg/day in EXIST-2. Estimated glomerular filtration rate (eGFR) and creatinine levels were assessed at baseline, at Weeks 2, 4, 6, 8, 12 and 18, then every 3 months thereafter. Proteinuria was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.

RESULTS:

A total of 111 patients from EXIST-1 and 112 patients from EXIST-2 were included in this analysis. Respective mean ages at EVE initiation were 10.5 [standard deviation (SD) 6.45] and 33.2 (SD 10.29) years, and 3.6% and 37.5% of patients had undergone prior renal intervention. Mean baseline eGFR was 115 and 88 mL/min/1.73 m2 in EXIST-1 and EXIST-2, respectively. Overall, mean eGFR remained stable over time in both studies, with an decline in renal function mostly confined to some patients with severely compromised renal function before treatment. Patients with prior renal intervention exhibited low eGFR values throughout the study. The incidence of proteinuria increased after initiating treatment with EVE and was mostly Grade 1/2 in severity, with Grade 3 proteinuria reported in only two patients. Measurements of proteinuria were limited by the use of urine dipstick tests.

CONCLUSIONS:

The use of EVE does not appear to be nephrotoxic in patients with SEGA or renal angiomyolipoma associated with TSC and may preserve renal function in most patients. 

Li S, Zhang Y, Wang Z, Yang Y, Gao W, Li D, Wei J. Genotype-phenotype correlation of patients with tuberous sclerosis complex-associated renal angiomyolipoma: a descriptive study. Hum Pathol. 2018 Jul 20. pii:S0046-8177(18)30284-3. doi: 10.1016/j.humpath.2018.07.017. [Epub ahead of print]

Abstract

TSC2 gene mutation was repeatedly reported associated with a more severe phenotype in patients of tuberous sclerosis complex (TSC). Our current study aims to further explore whether there is such a correlation in patients with TSC-associated renal angiomyolipoma (TSC-RAML). TSC1/TSC2 gene mutation was screened by high throughput sequencing in 25 TSC-RAML patients from two medical centers. Clinical data were also carefully collected. Linear-regression analysis and student t-test were conducted by IBM SPSS Statistics Version 21.0 to analyze the genotypic-phenotypic relationship. The results indicated a high level of TSC gene mutation (80%, 20/25) in TSC-RAML patients, with higher frequency of TSC2 mutation (68%, 17/25) than TSC1 mutation (12%, 3/25). Seven novel mutation sites were detected in this study. In general, there were no significant correlations between tumor size and age (r=0.134, P=0.522), hemoglobin (r=0.255, P=0.219) and serum creatinine (r=0.043, P=0.839). Patients with larger tumor size have higher risk of bleeding. Specially, it was higher level of hemoglobin in patients with TSC1 mutation than ones with TSC2 mutation and without TSC mutation (P<0.05). However, no difference was found in either tumor size or serum creatinine by TSC mutation genes (P>0.05). Furthermore, no difference was found in tumor size, hemoglobin and serum creatinine by TSC mutation types (P>0.05). In conclusion, TSC-RAML is TSC2 mutation dominant, with the individual differences varying greatly. No definite genotype-phenotype correlation exists in patients with TSC-RAML, and it needs to be further explored.