Aan de hand van de ziektegeschiedenis van een patiënte met diabetes die in 1980 in dit tijdschrift als neonaat werd beschreven,1 laten wij het belang van levensloopgeneeskunde in de... Show moreAan de hand van de ziektegeschiedenis van een patiënte met diabetes die in 1980 in dit tijdschrift als neonaat werd beschreven,1 laten wij het belang van levensloopgeneeskunde in de diabeteszorgketen zien. De ziektegeschiedenis illustreert dat er door de jaren heen sprake van aanpassingen in de diagnostiek en behandeling, gebaseerd op voortschrijdend inzicht. Show less
Bayley, J.P.; Bausch, B.; Jansen, J.C.; Hensen, E.F.; Tuin, K. van der; Corssmit, E.P.M.; ... ; Neumann, H.P.H. 2021
Background Traditional genotype-phenotype correlations for the succinate dehydrogenase-complex II (SDH) genes link SDHB variants to thoracic-abdominal pheochromocytoma-paraganglioma (PPGL) and SDHD... Show moreBackground Traditional genotype-phenotype correlations for the succinate dehydrogenase-complex II (SDH) genes link SDHB variants to thoracic-abdominal pheochromocytoma-paraganglioma (PPGL) and SDHD variants to head and neck paraganglioma (HNPGL). However, in a recent study we found strong and specific genotype-phenotype associations for SDHD variants. In the present study we zoom in on the genotype-phenotype associations of SDHB gene variants, considering the impact of individual gene variants on disease risk and risk of malignancy. Methods We analysed two large independent data sets, including a total of 448 patients with PPGL and HNPGL, and studied the association of missense or truncating SDHB variants with tumour incidence, age of onset and malignancy risk using binomial testing and Kaplan-Meier analysis. Results Compared with missense variants, truncating SDHB variants were significantly and consistently more common in patients with PPGL, by a 20 percentage point margin. Malignancy was also significantly more common in truncating versus missense variant carriers. No overall differences in age of PPGL onset were noted between carriers of the two variant types, although some individual variants may differ in certain cases. Missense variants were marginally over-represented among patients with HNPGL, but the difference was not statistically significant. Conclusion SDHB truncating variants convey an elevated risk for development of both PPGL and malignancy compared with missense variants. These results further support earlier robust associations between truncating variants and PPGL, and also suggest that the two variant types differ in their impact on complex II function, with PPGL/HNPGL tissues displaying differing sensitivities to changes in complex II function. Show less
We report a case of a 22-year-old female patient who was diagnosed with a cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC). While at early ages this thyroid cancer variant is... Show moreWe report a case of a 22-year-old female patient who was diagnosed with a cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC). While at early ages this thyroid cancer variant is highly suggestive for familial adenomatous polyposis (FAP), there was no family history of FAP. In the tumor biallelic, inactivating APC variants were identified. The patient tested negative for germline variants based on analysis of genomic DNA from peripheral blood leukocytes. Somatic mosaicism was excluded by subsequent deep sequencing of leukocyte and normal thyroid DNA using next generation sequencing (NGS). This report presents a rare sporadic case of CMV-PTC, and to the best of our knowledge the first featuring two somatic APC mutations underlying the disease, with an overview of CMV-PTC cases with detected APC and CTNNB1 pathogenic variants from the literature. 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
Context: DICER1 syndrome is a rare autosomal-dominantly inherited disorder that predisposes to a variety of cancerous and noncancerous tumors of mostly pediatric and adolescent onset, including... Show moreContext: DICER1 syndrome is a rare autosomal-dominantly inherited disorder that predisposes to a variety of cancerous and noncancerous tumors of mostly pediatric and adolescent onset, including differentiated thyroid carcinoma (DTC). DTC has been hypothesized to arise secondarily to the increased prevalence of thyroid hyperplastic nodules in syndromic patients.Objective: To determine somatic alterations in DICER1-associated DTC and to study patient outcomes.Design: Retrospective series.Setting: Tertiary referral centers.Patients: Ten patients with germline pathogenic DICER1 variants and early-onset DTC.Methods: Somatic DICER1 mutation analysis, extensive somatic DNA variant and gene fusion analyses were performed on all tumors.Results: Median age at DTC diagnosis was 13.5 years and there was no recurrent or metastatic disease (median follow-up, 8 years). All thyroid specimens showed diffuse nodular hyperplasia with at least one focus suspicious of DTC but without infiltrative growth, extrathyroidal extension, vascular invasion, or lymph node metastasis. Most of the individual nodules (benign and malignant) sampled from the 10 tumors harbored distinct DICER1 RNase IIIb hotspot mutations, indicating a polyclonal composition of each tumor. Furthermore, nine of 10 DICER1-related DTCs lacked well known oncogenic driver DNA variants and gene rearrangements.Conclusion: On the basis of our clinical, histological, and molecular data, we consider that most DICER1-related DTCs form a low-risk subgroup. These tumors may arise within one of multiple benign monoclonal nodules; thus, hemi-thyroidectomy or, more likely, total thyroidectomy may often be required. However, radioiodine treatment may be unnecessary given the patients' ages and the tumors' low propensity for metastases. Show less
Tuin, K. van der; Mensenkamp, A.R.; Tops, C.J.; Kunst, H.P.; Jansen, J.C.; Kleij-Corssmit, E.P. van der; ... ; Timmers, H.J. 2018
