Introduction In addition to catecholamines, pheochromocytomas and paragangliomas (PPGL) may secrete interleukin-6 (IL-6). IL-6 contributes to the development of unusual symptoms, which may hinder... Show moreIntroduction In addition to catecholamines, pheochromocytomas and paragangliomas (PPGL) may secrete interleukin-6 (IL-6). IL-6 contributes to the development of unusual symptoms, which may hinder the diagnosis. Patients and methods We report the clinical course and subsequent treatment of IL-6 producing PPGL in three patients from a single tertiary referral centre for PPGL patients in the Netherlands. Conclusion PPGL combined with persistent elevated inflammatory markers, either in the presence or absence of pyrexia, raised suspicion of IL-6 overproduction in these three patients. Although surgical resection of the tumour is the only curative treatment option, our case series adds to the accumulating evidence that alpha-blockers might be effective in these patients. Show less
Pheochromocytoma/paraganglioma (PPGL)-induced catecholamine crisis is a rare endocrine emergency leading to life-threatening hemodynamic instability causing end-organ damage or dysfunction. As it... Show morePheochromocytoma/paraganglioma (PPGL)-induced catecholamine crisis is a rare endocrine emergency leading to life-threatening hemodynamic instability causing end-organ damage or dysfunction. As it is associated with a significant mortality rate of approximately 15%, recognizing the signs and symptoms and making the appropriate diagnosis are critical. For this purpose, we report the clinical course of the crisis in four out of a total of six patients with a PPGL crisis from a cohort of 199 PPGL patients of a single tertiary referral center for PPGL patients in the Netherlands diagnosed between 2002 and 2020. Successful treatment of a PPGL crisis demands prompt diagnosis, vigorous pharmacological therapy, and emergency tumor removal if the patient continues to deteriorate. Show less
Context: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors in which altered central metabolism appears to be a major driver of tumorigenesis, and many PPGL genes encode... Show moreContext: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors in which altered central metabolism appears to be a major driver of tumorigenesis, and many PPGL genes encode proteins involved in the tricarboxylic acid (TCA) cycle.Objective/design: While about 40% of PPGL cases carry a variant in a known gene, many cases remain unexplained. In patients with unexplained PPGL showing clear evidence of a familial burden or multiple tumors, we aimed to identify causative factors using genetic analysis of patient DNA and functional analyses of identified DNA variants in patient tumor material and engineered cell lines.Patients and Setting: Patients with a likely familial cancer burden of pheochromocytomas and/or paragangliomas and under investigation in a clinical genetic and clinical research setting in university hospitals.Results: While investigating unexplained PPGL cases, we identified a novel variant, c.1151C>T, p.(Pro384Leu), in exon 14 of the gene encoding dihydrolipoamide S-succinyltransferase (DLST), a component of the multi-enzyme complex 2-oxoglutarate dehydrogenase. Targeted sequence analysis of further unexplained cases identified a patient carrying a tumor with compound heterozygous variants in DLST, consisting of a germline variant, c.1121G>A, p.(Gly374Glu), together with a somatic missense variant identified in tumor DNA, c.1147A>G, p.(Thr383Ala), both located in exon 14. Using a range of in silico and functional assays we show that these variants are predicted to be pathogenic, profoundly impact enzyme activity, and result in DNA hypermethylation.Conclusions: The identification and functional analysis of these DLST variants further validates DLST as an additional PPGL gene involved in the TCA cycle. Show less
This thesis, describes investigations of the genetic background of a wide variety of rare endocrine tumors, including those of the thyroid, parathyroid, adrenal and paraganglia. In the first part,... Show moreThis thesis, describes investigations of the genetic background of a wide variety of rare endocrine tumors, including those of the thyroid, parathyroid, adrenal and paraganglia. In the first part, our studies focus on the role of molecular testing in diagnostics and treatment decision making in patients with DICER1 syndrome or advanced radioactive iodine refractory thyroid cancer. In the second part, we investigated the of genetic background of pediatric non-medullary thyroid carcinoma. In the third part we focused on genetic counseling in the following endocrine tumor predisposition syndromes: CDC73-related disorder, SDHA-associated paraganglioma and MEN2a syndrome. Our studies contributed to the debate on accurate estimation of disease penetrance. In order to provide answers to the questions - “Why do I have cancer? Are other relatives at risk? And if so, can we prevent cancer?” - patient- and family centered endocrine cancer care encourages active collaboration between the departments of endocrinology, oncology, surgery, pathology, chemistry, radiology, nuclear medicine and clinical genetics. Show less
Onderzoek naar de klinische karakteristieken van patiënten met paragangliomen. Hierbij ligt de nadruk op mutaties in de SDH-genen. Onderdeel van dit research project in een nationale multicenter... Show moreOnderzoek naar de klinische karakteristieken van patiënten met paragangliomen. Hierbij ligt de nadruk op mutaties in de SDH-genen. Onderdeel van dit research project in een nationale multicenter studie waaraan de academische centra in Nederland deelnemen, om zo alle SDHB mutatie dragers te kunnen bundelen. Zo kan de genotype-fenotype relatie van deze zeldzame mutatie worden onderzocht in een cohort van ongeveer 200 mutatiedragers. Een ander onderdeel van dit PhD research project is het onderzoeken of SDH-mutaties ook geassocieerd zijn met ándere tumoren. Het blijkt namelijk dat SDH-mutatiedragers niet alleen paragangliomen ontwikkelen, maar bijvoorbeeld ook renaalcelcarcinoom of schildklierkanker. Tevens wordt de behandeling van maligne paragangliomen en feochromocytomen met MIBG danwel chemotherapie in beeld gebracht door middel van een systematische review en meta-analyse betreffende deze twee therapieën. Show less
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
Flines, J. de; Jansen, J.; Elders, R.; Siemers, M.; Vriends, A.; Hes, F.; ... ; Corssmit, E. 2011
