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Purpose: Differences in syndromic manifestations of multiple endocrine neoplasia 2 A (MEN2A) between index and non-index patients are ill-defined., Methods: Cross-sectional analysis of 602 REarranged during Transfection (RET) carriers (156 index and 446 non-index patients) who underwent thyroidectomy, adrenalectomy, and/or parathyroidectomy between 1985 and 2022, stratified by mutational risk., Results: Index patients were 5.8-13.9 years older at thyroidectomy than non-index patients, at which point they had developed 10.6-14.4 mm larger medullary thyroid cancers. Correlations between index status and primary tumor size (ρ = 0.489-0.544) were stronger than correlations between index status and age at thyroidectomy (ρ = 0.359-0.438). For pheochromocytoma and primary hyperparathyroidism, no significant differences were noted. When stratified by time of surgery before vs. in the new millennium, age at thyroidectomy fell significantly only for non-index patients in the new millennium: from 28.6 to 21.2 years (moderate-high risk mutations; P = 0.049) and from 23.1 to 12.3 years (high-risk mutations; P < 0.001). All other inter-millennium comparisons did not reach statistical significance., Conclusion: These findings imply that differences between index and non-index patients impact the first syndromic manifestation without extending to subsequent syndromic manifestations. Because they exhibited similar age and tumor characteristics for the secondary and tertiary manifestations of MEN2A, screening for these syndromic components remains an integral element of MEN2A management in index and non-index patients alike. Wider use of population genomic screening may work to diminish the observed disparities between index and non-index patients going forward., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: In clinical practice, false-positive results in biochemical testing for suspected pheochromocytoma/paraganglioma (PPGL) are not infrequent and may lead to unnecessary examinations. We aimed to evaluate the role of the clonidine suppression test (CST) in the era of analyses of plasma-free metanephrines for the diagnosis or exclusion of PPGL in patients with adrenal tumours and/or arterial hypertension., Design and Methods: This single-centre, prospective trial investigated the use of CST in 60 patients with suspected PPGL associated with out-patient elevations of plasma normetanephrine (NMN) and/or metanephrine (MN), in most cases accompanied with hypertension or an adrenal mass. Measurements of plasma catecholamines and free metanephrines were performed by liquid chromatography with electrochemical detection and tandem mass spectrometry, respectively., Results: Forty-six patients entered final analysis (n = 20 with PPGL and n = 26 with a nonfunctional adrenal mass and/or hypertension). CST reliably excluded false-positive baseline NMN results with a specificity of 100%. The sensitivity of CST improved from 85% to 94% when tumours with isolated MN increase (n = 3) were not considered. In patients with elevated baseline NMN (n = 24), CST correctly identified all patients without PPGL. Patients with falsely elevated baseline NMN results (n = 7, 26.9%) exhibited increases of baseline NMN up to 1.7-fold above the upper reference limit., Conclusion: CST qualifies as a useful diagnostic tool for differential diagnosis of borderline elevated plasma-free NMN in patients with suspected PPGL. In this context, CST helps to correctly identify all false-positive NMN screening results., (© 2022 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

There are no data on the impact of parent-of-origin effects on the expression of multiple endocrine neoplasia type 2A (MEN2A). The present study aimed to explore effects of parent-of-origin and offspring gender in MEN2A. In total, 224 carriers harbored heterozygous RET (REarranged during Transfection) p.Cys634 missense variants, for 169 of whom information on parent-of-origin gender was available. Altogether, offspring from affected fathers harbored more often node metastases from medullary thyroid cancer (45 vs. 19%; P = 0.006) and bilateral pheochromocytoma (24 vs. 10%; P = 0.021) than offspring from affected mothers. The former also also tended to be older at most recent follow-up (medians of 21 vs. 14 years; P = 0.056) and tended to have more often pheochromocytoma (33 vs. 19 yrs.; P = 0.051) and primary hyperparathyroidism (13 vs. 4%; P = 0.090) than the latter. Daughters from affected fathers harbored more often node metastases (39 vs. 15%; P = 0.043) than daughters from affected mothers. This difference decreased in male offspring when sons from affected fathers were compared with sons from affected mothers (52 vs. 40%; P = 0.111). There was also a slight deficit of male offspring: 1.1 sons each per affected mother and father vs. 1.2 daughters per affected mother and 1.4 daughters per affected father. These data suggest a parent-of-origin effect in MEN2A, warranting international collaborative research., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

123/131 I-metaiodobenzylguanidine (MIBG) scintigraphy has shown a high specificity for imaging pheochromocytoma and paraganglioma, but with low sensitivity because of low spatial resolution. 124 I-MIBG PET may be able to overcome this limitation and improve the staging of patients with (suspected) pheochromocytoma. Methods: We analyzed the sensitivity, specificity, and positive and negative predictive values of 124 I-MIBG PET in 43 consecutive patients with suspected (recurrence of) pheochromocytoma using histopathologic ( n  = 25) and clinical validation ( n  = 18) as the standard of truth. Furthermore, we compared the detection rate of 124 I-MIBG PET versus contrast-enhanced (CE) CT on a per-patient and per-lesion basis in 13 additional patients with known metastatic malignant pheochromocytoma. Results: I-MIBG PET/CT was positive in 19 (44%) of 43 patients with suspected pheochromocytoma. The presence of pheochromocytoma was confirmed in 22 (51%) of 43. 124 I-MIBG PET/CT was positive in 19 (44%) of 43 patients with suspected pheochromocytoma. The presence of pheochromocytoma was confirmed in 22 (51%) of 43. 124 I-MIBG PET was positive in 11 (85%) of 13 patients with malignant pheochromocytoma. Combined 124 I-MIBG PET was positive in 11 (85%) of 13 patients with malignant pheochromocytoma. Combined 124 I-MIBG PET and CE CT detected 173 lesions, of which 166 (96%) and 118 (68%) were visible on 124 I-MIBG PET detects pheochromocytoma with high accuracy at initial staging and a high detection rate at restaging. Future assessment of Conclusion: 124 I-MIBG PET detects pheochromocytoma with high accuracy at initial staging and a high detection rate at restaging. Future assessment of 124 I-MIBG PET for treatment guidance, including personalized 131 I-MIBG therapy, is warranted., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: The objective of this study was to provide RET genotype-specific data on recurrent ipsilateral pheochromocytoma in multiple endocrine neoplasia type 2A (MEN2A), which are sparse., Methods: Kaplan-Meier analyses were performed to determine the risk of recurrent ipsilateral adrenalectomy after subtotal and total adrenalectomy in 221 carriers of RET p.Cys634 missense mutations., Results: Altogether, pheochromocytoma emerged in 112 of 442 adrenals at risk, for which 63 adrenals underwent total adrenalectomy and 49 adrenals subtotal adrenalectomy. After a mean (median) of 99 (132.9) months, 10 recurrent ipsilateral pheochromocytomas arose in 10 (20.4%) of 49 adrenal remnants. Seven of these 10 adrenal remnants were subjected to total adrenalectomy and 3 to another subtotal adrenalectomy. After 23 and 250 (mean/median 136.5) more months, 2 of the 3 remaining adrenal remnants gave rise to 2 further recurrent ipsilateral pheochromocytomas, which were removed by total adrenalectomy. When the rare publications in which carriers of RET p.Cys634 mutations made up 81-84% of MEN2A patients were combined with the present RET p.Cys634-specific series, the risk of recurrent ipsilateral pheochromocytoma was 6.7% (25 recurrent ipsilateral pheochromocytomas in 375 adrenal remnants), with a mean time interval of 146 months after initial subtotal adrenalectomy., Conclusion: Subtotal adrenalectomy is a viable treatment option for many carriers of RET p.Cys634 mutations who develop an initial pheochromocytoma. Although the adrenal remnant may give rise to recurrent ipsilateral pheochromocytoma after 8-11 years in up to 20% of patients, it is manageable very well in experienced hands, buying the patient valuable time off steroids., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The age-specific development of the three constituent components of multiple endocrine neoplasia type 2 (MEN 2) is incompletely characterized for many of the >30 causative rearranged during transfection (RET) mutations, which this genetic association study aimed to specify. Included in the study were 683 carriers of heterogeneous RET germline mutations: 53 carriers with 1 highest-risk mutation (codon 918); 240 carriers with 8 different high-risk mutations (codon 634); 176 carriers with 16 different intermediate-risk mutations (codon 609, 611, 618, 620, or 630); and 214 carriers with 6 different low-risk mutations (codon 768, 790, 804, or 891). There was a strong genotype-specific development of MEN 2 constituent components, with distinct age gradients from C cell disease to node negative medullary thyroid cancer (MTC), from node negative to node positive MTC, from node positive MTC to pheochromocytoma, and from pheochromocytoma to primary hyperparathyroidism. Primary hyperparathyroidism was not observed among the 53 MEN 2B patients who carried highest-risk mutations (age range: 0.5-50 years), of whom no more than 12 (23%) and 3 (6%) carriers were older than age 30 years and 35 years, respectively. The age-specific development of MTC differed significantly between the four RET risk categories, whereas the age-specific development of pheochromocytoma differed significantly only between the two strongest RET risk categories. No significant differences were noted in the development of primary hyperparathyroidism. These findings delineate age-specific disease manifestation corridors for the three constituent components of MEN 2 by RET genotype. These corridors are useful for initial risk assessment and organ-specific surveillance of newly identified RET carriers going forward. [ABSTRACT FROM AUTHOR]

Context: Early genetic association studies yielded too high risk estimates for multiple endocrine neoplasia (MEN2A), suggesting a need for extended surgery. Objective: The objective was to delineate temporal changes in MEN2A presentation by birth cohort analyses. Methods: Birth cohort analyses (10-year increments; ≤1950 to 2011-2020) of carriers of rearranged during transfection (RET) mutations who underwent surgery for MEN2A. Results: Included in this study were 604 carriers (155 index, 445 nonindex, 4 additional patients), with 237 carriers harboring high-risk mutations, 165 carriers moderate--high risk mutations, and 202 carriers low--moderate risk mutations. With increasing recency of birth cohorts, there was a continual decline in index patients from 41-74% to 0% (P < .001) and of medullary thyroid cancer (MTC) from 96-100% to 0-33% (P < .001). Node metastases diminished from 62-70% to 0% (P ≤ .001; high and low--moderate risk mutations), whereas biochemical cure after thyroidectomy surged from 17-33% to 100% (P ≤ .019; high and low--moderate mutations). Surgical interventions for MEN2A-related tumors were performed increasingly earlier, causing median carrier age to fall: from 51-63 to 3-5 years at thyroidectomy (P < .001); from 46-51 to 24-25 years at first adrenalectomy (P ≤ .013; high and moderate--high risk mutations); and from 43.5-66 to 16.5-32 years at parathyroidectomy. MTC diameters were more effectively decreased from 14-32 to 1-4 mm (P ≤ 002) than pheochromocytoma diameters (nonsignificant). Conclusion: These insights into MEN2A presentation, adjusted by birth year, illustrate the shift from reactive to preventative medicine, enabling less extensive risk-reducing surgery. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to delineate the age-dependent clinical penetr ance and expression of heterozygous rearranged during transfection (RET) missense mutations associated with multiple endocrine neoplas ia 2A (MEN2A) according to parental inheritance. Design: This was an observational study of RET carriers operated for MEN2A-associated tumors between 1985 and 2021. Methods: Kaplan-Meier time-to-event and multivariable Cox proportional hazards regression analyses were performed on node metastases from medullary thyroid cancer, pheochromocyt oma, bilateral pheochromocytoma, and primary hyperparathyroidism. Results: Some 405 (70.1%) of 578 patients carrying heterozygous MEN2A RET missense mutations had information about the parental inheritance of the trait. On Kaplan-Meier analysis, offspring who inherited the trait from the fathe r developed node metastases (Plog-rank = 0.007), pheochromocytoma (Plog-rank = 0.029), bilateral pheochromocytoma (Plog-rank = 0.002), and primary hyperparathyroidism (Plog-rank = 0.018) at a significantly younger age than offspring who inherited the trait from the mother. On multivariable Cox regre ssion, controlling for index status, offspring sex, and (where feasible) mutational risk, parental inheritance was cons istently associated with each MEN2A-associated tumor (hazard ratios (HR) = 1.7-1.8 for the earlier manifestations node metastases and phe ochromocytoma vs HR of 2.9-3.4 for the late manifestations bilateral pheochromocytoma and prim ary hyperparathyroidism). Herein, node metastases were 3.1- and 1.7-fold more closely associated with mutational risk (HR of 5.3 for high and 2.9 for moderate-high risk mutations vs low-moderate risk mutations) than parental inherit ance (HR = 1.7). Conclusion: These findings illustrate the importance of considering not just mutational risk but also parental inheritance when it comes to personalization of screening for a nd early detection of the various components of MEN2A-associated tumors. [ABSTRACT FROM AUTHOR]