This thesis aims to gain insight in the genetics, inheritance and tumor biology of head and neck paragangliomas, with a focus on SDHD and SDHAF2-related tumors. Mutations in SDHD and SDHAF2... Show moreThis thesis aims to gain insight in the genetics, inheritance and tumor biology of head and neck paragangliomas, with a focus on SDHD and SDHAF2-related tumors. Mutations in SDHD and SDHAF2 show a remarkable parent-of-origin dependent tumorigenesis in which tumor formation almost exclusively occurs following paternal transmission of the mutation. The Hensen model is discussed to explain this striking inheritance pattern seen in SDHD and SDHAF2-linked families. Show less
Paragangliomas are rare neoplasms that occur predominantly in the head and neck region. They originate from the neural crest derived cells within paraganglions, and are closely related to the... Show moreParagangliomas are rare neoplasms that occur predominantly in the head and neck region. They originate from the neural crest derived cells within paraganglions, and are closely related to the pheochromocytomas of the adrenal medulla. In contrast to other European countries, the majority of head and neck paraganglioma patients in the Netherlands suffer from hereditary paraganglioma syndrome, even if they present without a positive family history. The vast majority of Dutch patients carry one of only six founder mutations in genes encoding subunits of the mitochondrial succinate dehydrogenase, most notably in SDHD. SDHD-linked patients are characterized by a mean age at onset between 35-40 years, a high risk of multiple paragangliomas (73%), a risk of concurrent pheochromocytomas (13%) and extra-adrenal paragangliomas (8%), and a small risk of metastases (2%). The penetrance upon paternal transmission of SDHD mutations is high (87-100%). Interestingly, maternal transmission of SDHD mutations only rarely results in paraganglioma formation. This inheritance pattern is consistent with maternal imprinting, but there is ample evidence contradicting the imprinting of the SDHD gene itself. In the thesis, a model is discussed that explains this parent-of-origin-dependent inheritance by the involvement of an additional, imprinted tumor suppressor gene located, like SDHD, on chromosome 11. Show less
In this thesis we describe the genetic, biochemical and clinical characteristics of patients with head and neck paragangliomas (HNPGL). In the Netherlands, the majority of SDHx mutation carriers,... Show moreIn this thesis we describe the genetic, biochemical and clinical characteristics of patients with head and neck paragangliomas (HNPGL). In the Netherlands, the majority of SDHx mutation carriers, harbor a mutation in the SDHD gene. Twenty-nine percent of patients with HNPGL have increased urinary excretion of 3-methoxytyramine, indicating dopaminergic activity. Test sensitivity of plasma 3MT measurement equals the measurement of urinary deconjugated 3MT excretion. Only a minority of HNPGL patients have increased plasma chromogranin A levels. Therefore, the practical implications of the measurement of plasma chromogranin A levels are limited in HNPGL patients. Patients screened for pheochromocytomas, because of a hereditary predisposition, present with less signs and symptoms, lower urinary excretion rates of catecholamines, and smaller tumors than patients presenting with symptomatic pheochromocytomas. Despite these differences in biochemical activity and the sizes of the tumors, there is no difference in patients regarding peri-operative complications. Patients with bilateral carotid body tumors are at risk for developing sleep disordered breathing. Sleep disordered breathing is associated with increased carotid body output, which is reflected by increased chemosensitivity. Show less
Head and Neck Paragangliomas (HNP) are hypervascular tumours characterised by a slow growth pattern and a strong hereditary context that originate from the neural crest derived paraganglia, which... Show moreHead and Neck Paragangliomas (HNP) are hypervascular tumours characterised by a slow growth pattern and a strong hereditary context that originate from the neural crest derived paraganglia, which are associated with the autonomous nervous system and are situated at several locations in the head and neck region. Inactivating mutations in subunits of complex II (SDH) of the mitochondrial respiratory chain are responsible for hereditary tumours and have lead to a novel concept of mitochondrial tumoursupressor-genes and further insight in the intricate association of cellular oxygen sensing mechanisms and (pseudo)-hypoxia as environmental risk factors. However, further characterisation of the tumour biology is warranted for better understanding of the natural behaviour of HNP and possible identification clinicopathological parameters that could aid the clinician in his treatment decisions. In this thesis several studies on the molcular pathology of HNP are discussed including genotype-fenotype relations, the role of bFGF in tumourgenisis, the interplay between proliferation, cell cycle activity and apoptosis, and the nature of sustentacular cells in these apparent biphasic tumours. Additionally, in a clincal study the prevalence of synchronic or metachronic pheochromocytomas in patients with SDHD-linked HNP was determined. Show less
