The penetrance of MEN2 pheochromocytoma is not only determined by RET mutations

Castinetti, Frédéric; Maia, Ana Luiza; Pęczkowska, Mariola; Barontini, Marta; Hasse-Lazar, Kornelia; Links, Thera P.; Toledo, Rodrigo A.; Dvořáková, Šárka; Mian, Caterina; Bugalho, Maria João; Zovato, Stefania; Alevizaki, Maria; Kvachenyuk, А.M.; Bausch, Birke; Loli, Paola; Bergmann, Simona; Patócs, Attila; Pfeifer, Marija; Costa, Josefina Biarnes; Dobschuetz, Ernst von; Letizia, Claudio; Valk, Gerlof D.; Barczyński, Marcin; Czetwertyńska, Małgorzata; Plukker, John; Sartorato, Paola; Zelinka, Tomáš; Vlček, Petr; Yaremchuk, Svetlana; Weryha, G.; Canu, Letizia; Wohllk, Nelson; Sébag, F.; Walz, Martin K.; Eng, Charis; Neumann, Hartmut P. H.

doi:10.1530/erc-17-0189

Cited by 21 publications

(15 citation statements)

References 10 publications

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“…Mucha et al reported that the penetrance and age at diagnosis of pheochromocytoma were correlated with medullary thyroid carcinoma aggressiveness, and both correlated with RET mutation position: for instance, the penetrance was estimated at 47% in RET exon 11 vs 30% in exon 10 carriers (Mucha et al 2017). Castinetti et al showed that even in RET codon 634 mutation (the most highly penetrant) carriers, the penetrance could be highly variable depending on the geographical area of the patient's origin, suggesting the roles of yet-unknown modifiers (Castinetti et al 2017), while Siqueira et al showed that RET polymorphisms had a modifying effect on the age at pheochromocytoma diagnosis (Siqueira et al 2014). Of note, despite the fact that pheochromocytoma can be quite frequent in RET mutation carriers, Thosani et al emphasized the lack of increased mortality in RET mutation carriers regularly screened for pheochromocytoma (Thosani et al 2013).…”

Section: Multiple Endocrine Neoplasia Typementioning

confidence: 99%

65 YEARS OF THE DOUBLE HELIX: Genetics informs precision practice in the diagnosis and management of pheochromocytoma

Neumann¹,

Young²,

Krauß³

et al. 2018

Endocrine-Related Cancer

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Although the authors of the present review have contributed to genetic discoveries in the field of pheochromocytoma research, we can legitimately ask whether these advances have led to improvements in the diagnosis and management of patients with pheochromocytoma. The answer to this question is an emphatic ! In the field of molecular genetics, the well-established axiom that familial (genetic) pheochromocytoma represents 10% of all cases has been overturned, with>35% of cases now attributable to germline disease-causing mutations. Furthermore, genetic pheochromocytoma can now be grouped into five different clinical presentation types in the context of the ten known susceptibility genes for pheochromocytoma-associated syndromes. We now have the tools to diagnose patients with genetic pheochromocytoma, identify germline mutation carriers and to offer gene-informed medical management including enhanced surveillance and prevention. Clinically, we now treat an entire family of tumors of the paraganglia, with the exact phenotype varying by specific gene. In terms of detection and classification, simultaneous advances in biochemical detection and imaging localization have taken place, and the histopathology of the paraganglioma tumor family has been revised by immunohistochemical-genetic classification by gene-specific antibody immunohistochemistry. Treatment options have also been substantially enriched by the application of minimally invasive and adrenal-sparing surgery. Finally and most importantly, it is now widely recognized that patients with genetic pheochromocytoma/paraganglioma syndromes should be treated in specialized centers dedicated to the diagnosis, treatment and surveillance of this rare neoplasm.

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Section: Multiple Endocrine Neoplasia Typementioning

confidence: 99%

65 YEARS OF THE DOUBLE HELIX: Genetics informs precision practice in the diagnosis and management of pheochromocytoma

Neumann¹,

Young²,

Krauß³

et al. 2018

Endocrine-Related Cancer

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“…A strong genotype/ phenotype correlation thus exists for PHEO penetrance in MEN2 patients. However, we recently reported that the penetrance of PHEO in MEN2 was variable depending on the geographic area, with an age at first diagnosis of PHEO significantly higher in South America than that in Europe (Castinetti et al 2017). The American Thyroid Association (ATA) guidelines recommended screening for PHEO beginning at 11 years for children in the ATAhigh and highest risk (RET codons 634, 883 and 918) and 16 years in the ATA-moderate risk (all the other codons) (Wells et al 2015).…”

Section: Men2 Pheomentioning

confidence: 99%

Looking beyond the thyroid: advances in the understanding of pheochromocytoma and hyperparathyroidism phenotypes in MEN2 and of non-MEN2 familial forms

Guérin¹,

Romanet²,

Taïeb³

et al. 2018

Endocrine-Related Cancer

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Over the last years, the knowledge of MEN2 and non-MEN2 familial forms of pheochromocytoma (PHEO) has increased. In MEN2, PHEO is the second most frequent disease: the penetrance and age at diagnosis depend on the mutation of Given the prevalence of bilateral PHEO (50% by age 50), adrenal sparing surgery, aimed at sparing a part of the adrenal cortex to avoid adrenal insufficiency, should be systematically considered in patients with bilateral PHEO. Non-MEN2 familial forms of PHEO now include more than 20 genes: however, only small phenotypic series have been reported, suggesting that phenotypic features of isolated hereditary PHEO must be better explored, and follow-up series are needed to better understand the outcome of patients carrying mutations of these genes. The first part of this review will mainly focus on these points. In the second part, a focus will be given on MEN2 and non-MEN2 familial forms of hyperparathyroidism (HPTH). Again, the management of MEN2 HPTH should be aimed at curing the disease while preserving an optimal quality of life by a tailored parathyroidectomy. The phenotypes and outcome of MEN1-, MEN4- and HRPT2-related HPTH are briefly described, with a focus on the most recent literature data and is compared with familial hypocalciuric hypercalcemia.

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“…As patient 1 was of Lebanese origin (immigrated to Denmark at four years of age) and patient 2 of Danish origin, influence of ethnic, and geographical factors cannot be completely ruled out. Even though other studies have found geographical differences in pheochromocytoma of MEN 2A and survival of MEN 2B patients, the issue remains hypothetical (57,58).…”

Section: Discussionmentioning

confidence: 92%

Variability in Medullary Thyroid Carcinoma in RET L790F Carriers: A Case Comparison Study of Index Patients

et al. 2020

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Background: Previous studies have suggested that the variability in age of onset and aggressiveness of medullary thyroid carcinoma (MTC) in patients with multiple endocrine neoplasia type 2A (MEN 2A) carrying the same REarranged during Transfection (RET) mutation may be caused by additional RET germline variants or somatic variants. Methods: This study was a retrospective case comparison study of all MEN 2A index patients (n = 2) with the RET L790F germline mutation in Denmark. Whole blood and MTC tissue were analyzed for RET germline variants and other somatic variants (>500), respectively. Results: Patient 1 presented with MTC (T1aN1bM0) at age 14 years, while patient 2 presented with MTC (T1bN0M0) at age 70 years. No germline RET germline variants nor other variants were found to explain this MTC variability. Conclusions: We could not confirm the previously reported finding of a somatic RET variant as likely responsible for the early onset and aggressiveness of MTC in a RET germline mutation carrier. Also, we found no RET germline variants that could explain the MTC variability among our index patients. We did, however, identify a somatic FLT3 R387Q variant with an unknown potential as genetic modifier. Further large-scale studies are needed to investigate genetic modifiers in RET L790F carriers.

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The penetrance of MEN2 pheochromocytoma is not only determined by RET mutations

Cited by 21 publications

References 10 publications

65 YEARS OF THE DOUBLE HELIX: Genetics informs precision practice in the diagnosis and management of pheochromocytoma

65 YEARS OF THE DOUBLE HELIX: Genetics informs precision practice in the diagnosis and management of pheochromocytoma

Looking beyond the thyroid: advances in the understanding of pheochromocytoma and hyperparathyroidism phenotypes in MEN2 and of non-MEN2 familial forms

Variability in Medullary Thyroid Carcinoma in RET L790F Carriers: A Case Comparison Study of Index Patients

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