3P association (3PAs): Pituitary adenoma and pheochromocytoma/paraganglioma. A heterogeneous clinical syndrome associated with different gene mutations

Guerrero-Pérez, Fernando; Fajardo, Carmen; Vela, Enrique; Giménez-Palop, Olga; Gil, Arturo Lisbona; Martín, Tomás; Gonzalez, Natividad; Díez, Juan J.; Iglesias, Pedro; Robledo, Mercedes; Villabona, Carles

doi:10.1016/j.ejim.2019.08.005

Cited by 15 publications

(16 citation statements)

References 41 publications

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“…They detected a variant of uncertain significance in the RET gene. In the other patients with somatotrophinomas no mutations were found ( 13 ). Just as extremely rare as a head and neck PGL (HNPGL) in combination with a GH-secreting pituitary adenoma, TMEM127 mutations are rare causes of a HNPGL.…”

Section: Discussionmentioning

confidence: 99%

“…The first case of coexisting acromegaly and PCC was described in 1952 ( 12 ). Meanwhile the term ‘the three P association’ (’3PA’) has been coined to focus on the association of pituitary adenoma and PCC/PGL and recently a possible causality is being discussed ( 1 , 13 ). Up to now less than 100 patients with 3PAs’ had been reported and to our knowledge this is the first case of a patient with clinical manifestation of an acromegaly and a paraganglioma with evidence of a TMEM127 variant (c245–10C>G), albeit the clinical significance of this variant is uncertain.…”

Section: Introductionmentioning

confidence: 99%

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Identification of a TMEM127 variant in a patient with paraganglioma and acromegaly

Stütz

Korbonits

Kothbauer

et al. 2020

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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Summary The coincidence of a pheochromocytoma or paraganglioma and a pituitary adenoma in the same patient is a rare condition. In the last few years SDHx and MAX mutations have been identified and discussed as a potential causal connection in cases of coincidence. We describe a case of a middle-aged female patient which presented with acromegaly, a growth hormone-secreting pituitary adenoma and a symptomatic neck paraganglioma. The patient was cured by surgery from both the pituitary tumour and the paraganglioma and is well after ten years follow-up. Due to the unusual coexistence of two neuroendocrine tumours, further molecular genetic testing was performed which revealed a variant in the TMEM127 gene (c245-10C>G). Learning points: Pheochromocytoma/paraganglioma and coexisting functioning pituitary adenoma are a very rare condition. An appropriate treatment of each tumour entity with a multi-disciplinary approach and regular follow-up is needed. The possibility of a hereditary disease should be considered and genetic workup is recommended. Genetic testing should focus primarily on the genes with mutations related to pheochromocytomas and paragangliomas. Next-generation sequencing with multi-gene panel testing is the currently suggested strategy. Genes associated with paragangliomas and pituitary adenomas are SDHA, SDHB, SDHC, SDHD, SDHAF2, MAX and MEN1, while case reports with VHL, RET and NF1 may represent coincidences. Variants of uncertain significance may need ongoing vigilance, in case novel data become available of these variants.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of a TMEM127 variant in a patient with paraganglioma and acromegaly

Stütz

Korbonits

Kothbauer

et al. 2020

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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“…The specificity or sensitivity of 68 Ga-DOTATATE PET/CT for PHEO in MEN1 in unknown. A recently described rare syndrome of pituitary adenomas plus PHEO/paraganglioma (3PAs) has been associated with mutations in SDHB (cluster 1) and RET (cluster 2), which are two of the most prevalent germline mutations in patients with PHEO/paraganglioma (20). A report of a 54-year-old male patient with acromegaly and incidentally identified bilateral PHEO had a heterozygous germline variant of uncertain significance in MEN1 (c.1618C > T; p.Pro540Ser) (20).…”

Section: Discussionmentioning

confidence: 99%

“…A recently described rare syndrome of pituitary adenomas plus PHEO/paraganglioma (3PAs) has been associated with mutations in SDHB (cluster 1) and RET (cluster 2), which are two of the most prevalent germline mutations in patients with PHEO/paraganglioma (20). A report of a 54-year-old male patient with acromegaly and incidentally identified bilateral PHEO had a heterozygous germline variant of uncertain significance in MEN1 (c.1618C > T; p.Pro540Ser) (20). Additional cases with clinical history suggesting MEN1 (prior to the MEN1 gene discovery in 1997) include PHEO combined most commonly with hyperparathyroidism, gastrinoma and/or acromegaly (Table 2) (21,22,23,24).…”

Section: Discussionmentioning

confidence: 99%

18F-FDOPA PET/CT accurately identifies MEN1-associated pheochromocytoma

Tepede

Welch

Lee

et al. 2020

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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Summary Pheochromocytoma (PHEO) in multiple endocrine neoplasia type 1 (MEN1) is extremely rare. The incidence is reported as less than 2%. We report a case of a 76-year-old male with familial MEN1 who was found to have unilateral PHEO. Although the patient was normotensive and asymptomatic, routine screening imaging with CT demonstrated bilateral adrenal masses. The left adrenal mass grew from 2.5 to 3.9 cm over 4 years with attenuation values of 9 Hounsfield units (HU) pre-contrast and 15 HU post-contrast washout. Laboratory evaluation demonstrated an adrenergic biochemical phenotype. Both 18F-fluorodeoxyglucose (18F-FDG) PET/CT and 123I-metaiodobenzylguanidine (123I-mIBG) scintigraphy demonstrated bilateral adrenal uptake. In contrast, 18F-fluorodihydroxyphenylalanine (18F-FDOPA) PET/CT demonstrated unilateral left adrenal uptake (28.7 standardized uptake value (SUV)) and physiologic right adrenal uptake. The patient underwent an uneventful left adrenalectomy with pathology consistent for PHEO. Post-operatively, he had biochemical normalization. A review of the literature suggests that adrenal tumors >2 cm may be at higher risk for pheochromocytoma in patients with MEN1. Despite a lack of symptoms related to catecholamine excess, enlarging adrenal nodules should be biochemically screened for PHEO. 18F-FDOPA PET/CT may be beneficial for localization in these patients. Learning points: 18F-FDOPA PET/CT is a beneficial imaging modality for identifying pheochromocytoma in MEN1 patients. Adrenal adenomas should undergo routine biochemical workup for PHEO in MEN1 and can have serious peri-operative complications if not recognized, given that MEN1 patients undergo frequent surgical interventions. MEN1 is implicated in the tumorigenesis of PHEO in this patient.

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“…Succinate dehydrogenase is part of the mitochondrial complex II and plays a significant role in energy production through the Krebs cycle and the respiratory chain through electron transfer [73]. Additional studies have further contributed in the genetic spectrum of the disease, by identifying additional genetic causes of the association (SDHA, SDHAF2, VHL, MEN1, RET and MAX) [74][75][76][77][78]. The presenting pituitary tumors are more commonly PRL-or GH-secreting or non-functioning adenomas, but they are thought to be more aggressive in presentation and more likely to be resistant to standard therapy [77].…”

Section: P Association (3pas)mentioning

confidence: 99%

The Genetics of Pituitary Adenomas

Tatsi

Stratakis

2019

JCM

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The genetic landscape of pituitary adenomas (PAs) is diverse and many of the identified cases remain of unclear pathogenetic mechanism. Germline genetic defects account for a small percentage of all patients and may present in the context of relevant family history. Defects in AIP (mutated in Familial Isolated Pituitary Adenoma syndrome or FIPA), MEN1 (coding for menin, mutated in Multiple Endocrine Neoplasia type 1 or MEN 1), PRKAR1A (mutated in Carney complex), GPR101 (involved in X-Linked Acrogigantism or X-LAG), and SDHx (mutated in the so called "3 P association" of PAs with pheochromocytomas and paragangliomas or 3PAs) account for the most common familial syndromes associated with PAs. Tumor genetic defects in USP8, GNAS, USP48 and BRAF are some of the commonly encountered tissue-specific changes and may explain a larger percentage of the developed tumors. Somatic (at the tumor level) genomic changes, copy number variations (CNVs), epigenetic modifications, and differential expression of miRNAs, add to the variable genetic background of PAs.

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3P association (3PAs): Pituitary adenoma and pheochromocytoma/paraganglioma. A heterogeneous clinical syndrome associated with different gene mutations

Cited by 15 publications

References 41 publications

Identification of a TMEM127 variant in a patient with paraganglioma and acromegaly

Identification of a TMEM127 variant in a patient with paraganglioma and acromegaly

18F-FDOPA PET/CT accurately identifies MEN1-associated pheochromocytoma

The Genetics of Pituitary Adenomas

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