Are neuroendocrine tumours a feature of tuberous sclerosis? A systematic review

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterised by the development of multiple hamartomas in numerous organs. It is caused by mutations of two tumour suppressor genes, TSC1 on chromosome 9q34 and TSC2 on chromosome 16p13.3, which encode for hamartin and tuberin respectively. The interaction between these two proteins, the tuberin-hamartin complex, has been shown to be critical to multiple intracellular signalling pathways, especially those controlling cell growth and proliferation. TSC may affect skin, central nervous system, kidneys, heart, eyes, blood vessels, lung, bone and gastrointestinal tract. Small series and case reports have documented that in tuberous sclerosis patients many endocrine system alterations might occur, affecting the function of the pituitary, parathyroid and other neuroendocrine tissue. There have been scattered reports of the involvement of such tissue in the pathological process of TSC, but no systematic review as to whether this is a true association. We have therefore systematically assessed all available published literature in this area. We conclude that there may be an association with pituitary and parathyroid tumours, and two recent descriptions of Cushing's disease are especially intriguing. However, the evidence seems more firm in the case of islet cell tumours, particularly insulinomas. As these latter may cause changes in mental state that may be confused with the cerebral manifestations of TSC per se, it is particularly important for physicians working with these patients to be aware of the putative and indeed likely association.

Systematic comparison of sporadic and syndromic pancreatic islet cell tumors

“…In contrast, pancreatic ICTs are typical component tumors of MEN1 and VHL. Very rarely, ICTs have also been reported in neurofibromatosis type 1 and tuberous sclerosis complex , Dworakowska & Grossman 2009). However, studies on large series of patients with systematic molecular genetic analyses for germline mutations in the genes MEN1 and VHL were pending.…”

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

“…Amplification, overexpression or activation of PKB has been observed in ovarian, pancreatic, hepatocellular, mammary, prostate and colorectal carcinomas (Altomare and Testa, 2005). In neuroendocrine tumors (NETs), derived from neuroendocrine cells scattered throughout the body, for example, in the pancreas, stomach, (para) thyroid and pituitary glands, overexpression of PKB and decreased expression of TSC2 and PTEN has been observed (Dworakowska and Grossman, 2009;Missiaglia et al, 2010). NETs have even been suggested to be a clinical feature of TSC (Dworakowska and Grossman, 2009).…”

Zebrafish as an innovative model for neuroendocrine tumors

“…This disorder is caused by loss-of-function mutations of the TSC1 or the TSC2 genes, which code for the proteins hamartin and tuberin respectively. Hamartin and tuberin constitute a tumor suppressor complex that negatively modulates mammalian target of rapamycin (mTOR) signaling, a critical pathway in the regulation of cell proliferation and angiogenesis in several tumors, notably in NETs (Dworakowska & Grossman 2009). Kim et al (2011) developed a model system of TSC by introducing a premature stop codon in the zebrafish tsc2 gene.…”