Abstract
Phakomatoses encompass a group of rare genetic diseases, such as von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1), tuberous sclerosis complex (TSC) and Cowden syndrome (CS). These disorders are due to molecular abnormalities on the RAS-PI3K-Akt-mTOR pathway for NF1, TSC and CS, and to hypoxia sensing for VHL. Phakomatoses share some phenotypic traits such as neurological, ophthalmological and cutaneous features. Patients with these diseases are also predisposed to developing multiple endocrine tissue tumors, e.g., pheochromocytomas/paragangliomas are frequent in VHL and NF1. All forms of phakomatoses except CS may be associated with digestive neuroendocrine tumors. More rarely, thyroid cancer and pituitary or parathyroid adenomas have been reported. These susceptibilities are noteworthy, because their occurrence rate, prognosis and management differ slightly from the sporadic forms. The aim of this review is to summarize current knowledge on endocrine glands tumors associated with VHL, NF1, TSC, and CS, especially neuroendocrine tumors and pheochromocytomas/paragangliomas. We particularly detail recent advances concerning prognosis and management, especially parenchyma-sparing surgery and medical targeted therapies such as mTOR, MEK and HIF-2 α inhibitors, which have shown truly encouraging results.
Highlights
Phakomatoses are a group of systemic diseases linked to ectodermal dysembryogenesis
After a brief review of the pathophysiology of common forms of phakomatoses, we describe the clinical features of endocrine tumors associated with them and focus on their specific features compared with sporadic counterparts; time of occurrence, clinical expression and prognosis can differ slightly
Phacomatoses are a group of rare diseases that can be associated with neoplasia of the endocrine glands
Summary
Phakomatoses are a group of systemic diseases linked to ectodermal dysembryogenesis. The term comes from the Greek noun phakos (jakός, meaning “lentil” or “spot”) and the word termination -oma (for “tumor”), which refer to cutaneous birthmarks, i.e. hamartomas. - von Hippel-Lindau disease (VHL), - tuberous systemic complex (TSC), - and Cowden syndrome (CS). The prevalence is, less than 1/2,000 people These rare diseases were clinically described in the 19th century by famous physicians such as the pathologist Friedrich Daniel von Recklinghausen, and the ophthalmologist Eugen von Hippel, both from Germany, Arvid Lindau, a Swedish pathologist and Désiré-Magloire Bourneville, a French neurologist. The hereditary nature of these syndromes was predicted early on, their molecular basis was only elucidated at the end of the 20th century by means of genetic developments and the characterization of the Ras-PI3K-Akt-mTOR pathway in NF1, TSC, and CS, as well as of the hypoxia signaling pathway in VHL. Ophthalmological and cutaneous features, patients with phakomatoses are predisposed to developing tumors of the endocrine glands, with different spectrums for each disease (Figure 1). We detail recent advances concerning the management of those tumors, especially focusing on parenchyma-sparing surgery in localized disease and pharmacological therapies targeting mTOR, MEK and HIF2-a in advanced/metastatic disease
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