Advances in risk-oriented surgery for multiple endocrine neoplasia type 2

in Endocrine-Related Cancer
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  • 1 Department of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany
  • 2 Department of General, Visceral and Transplantation Surgery, Section of Endocrine Surgery, University of Duisburg-Essen, Essen, Germany

Genetic association studies hinge on definite clinical case definitions of the disease of interest. This is why more penetrant mutations were overrepresented in early multiple endocrine neoplasia type 2 (MEN2) studies, whereas less penetrant mutations went underrepresented. Enrichment of genetic association studies with advanced disease may produce a flawed understanding of disease evolution, precipitating far-reaching surgical strategies like bilateral total adrenalectomy and 4-gland parathyroidectomy in MEN2. The insight into the natural course of the disease gleaned over the past 25 years caused a paradigm shift in MEN2: from the removal of target organs at the expense of greater operative morbidity to close biochemical surveillance and targeted resection of adrenal tumors and hyperplastic parathyroid glands. The lead time provided by early identification of asymptomatic MEN2 carriers under biochemical surveillance delimits a ‘window of opportunity’, within which (i) pre-emptive total thyroidectomy alone is adequate, circumventing morbidity attendant to central node dissection; (ii) subtotal ‘tissue-sparing’ adrenalectomy is sufficient, trading the risk of steroid dependency for the risk of a second pheochromocytoma in the adrenal remnant and (iii) parathyroidectomy is limited to enlarged glands, trading the risk of postoperative hypoparathyroidism for the risk of leaving behind hyperactive parathyroid glands. Future research should delineate further the mutation-specific, age-dependent penetrance of pheochromocytoma and primary hyperparathyroidism to refine the risk-oriented approach to MEN2. The sweeping changes in the management of MEN2 since the new millenium hold the hope that death and major morbidity from this uncommon disease can be eliminated in our lifetime.

Abstract

Genetic association studies hinge on definite clinical case definitions of the disease of interest. This is why more penetrant mutations were overrepresented in early multiple endocrine neoplasia type 2 (MEN2) studies, whereas less penetrant mutations went underrepresented. Enrichment of genetic association studies with advanced disease may produce a flawed understanding of disease evolution, precipitating far-reaching surgical strategies like bilateral total adrenalectomy and 4-gland parathyroidectomy in MEN2. The insight into the natural course of the disease gleaned over the past 25 years caused a paradigm shift in MEN2: from the removal of target organs at the expense of greater operative morbidity to close biochemical surveillance and targeted resection of adrenal tumors and hyperplastic parathyroid glands. The lead time provided by early identification of asymptomatic MEN2 carriers under biochemical surveillance delimits a ‘window of opportunity’, within which (i) pre-emptive total thyroidectomy alone is adequate, circumventing morbidity attendant to central node dissection; (ii) subtotal ‘tissue-sparing’ adrenalectomy is sufficient, trading the risk of steroid dependency for the risk of a second pheochromocytoma in the adrenal remnant and (iii) parathyroidectomy is limited to enlarged glands, trading the risk of postoperative hypoparathyroidism for the risk of leaving behind hyperactive parathyroid glands. Future research should delineate further the mutation-specific, age-dependent penetrance of pheochromocytoma and primary hyperparathyroidism to refine the risk-oriented approach to MEN2. The sweeping changes in the management of MEN2 since the new millenium hold the hope that death and major morbidity from this uncommon disease can be eliminated in our lifetime.

Introduction

More than fifty years ago, the medical community witnessed the birth of a new hereditary endocrine syndrome encompassing medullary thyroid cancer (MTC) and pheochromocytoma: ‘Sipple syndrome’, named after the author of this seminal description (Sipple 1961). It is now commonly referred to as multiple endocrine neoplasia type 2 or MEN2, especially when complemented by primary hyperparathyroidism. This achievement was brought about by a combination of astute clinical observation (Sipple 1961, Williams 1965) coupled with advances in immunohistochemistry and hormonal assay technology.

Before that landmark event, individuals operated on for MTC would be misdiagnosed with papillary, follicular or undifferentiated thyroid cancer. Some individuals used to succumb to acute cardiovascular or cerebrovascular events, typically during childbirth masquerading as eclampsia or on invasive procedures, which in hindsight were ascribed to adrenergic hormonal excess from occult pheochromocytoma (Lips et al. 1981). ‘Sipple syndrome’, or MEN2A, came to attention in 1961 because it is a ‘noisy’ syndrome with as many patients initially identified based on the presence of hypercalcemia or pheochromocytoma as MTC, facilitating its recognition (Grubbs & Gagel 2015). Although most patients with fully penetrant MEN2 were ascertained quickly as having MEN2, patients featuring just one of the three syndromic constituents continued to be misdiagnosed with ‘sporadic’ disease.

The molecular era for MEN2 was ushered in with the discovery of RET (rearranged during transfection) as the susceptibility gene on chromosome 10q11.2 in 1993 (Donis-Keller et al. 1993, Mulligan et al. 1993). It became immediately apparent that DNA-based screening, revealing an individual’s genetic predisposition to MEN2, was superior to biochemical screening for subclinical disease (Lips et al. 1994, Wells et al. 1994, Learoyd et al. 1997, Dralle et al. 1998). Because genetic association studies are critically dependent on definite clinical case definitions of the disease of interest, more penetrant RET mutations were overrepresented in early MEN2 studies (Fig. 1; Eng et al. 1996, Frank-Raue et al. 2010, Machens et al. 2013a), including the International MEN2 Consortium analysis (Eng et al. 1996):

Figure 1
Figure 1

Prevalence of highest, high- and moderate-risk mutations in MEN2.

Citation: Endocrine-Related Cancer 25, 2; 10.1530/ERC-17-0202

  • Highest risk mutations in codon 918 (classic MEN2B; American Thyroid Association/ATA HST) (Wells et al. 2015);
  • High-risk mutations in codon 634 (classic MEN2A; ATA H) (Wells et al. 2015).

Initially underrepresented went moderate-risk mutations in codons 609, 611, 618, 620 and 630 (‘incomplete’ MEN2A; ATA MOD), whereas the weaker moderate-risk mutations in codons 768, 790, 804 and 891 (‘familial MTC’/FMTC; ATA MOD) were missed altogether. These weaker mutations were subsequently reported in 1995–1998 (Bolino et al. 1995, Eng et al. 1995, Hofstra et al. 1997, Berndt et al. 1998).

The enrichment of genetic association studies with individuals who manifest advanced disease (multifocal disease with involvement of multiple glands) is a methodological limitation (‘selection bias’), which is unavoidable when the susceptibility gene is unknown. Less well appreciated are the clinical ramifications of such enrichment for hereditary conditions like MEN2 in which every thyroid C-cell, adrenal medullary cell and parathyroid chief cell has inherited the predisposition to MTC, pheochromocytoma or pseudonodular parathyroid hyperplasia (Eng et al. 1996, Machens et al. 2003). These theoretical considerations, supported by histopathological evidence of diffuse multifocal disease in multiple glands in MEN2 (Lips et al. 1978) and fueled by reports about clusters of fatal outcome in certain MEN2 families (Lips et al. 1981), resulted in fairly extensive initial surgical strategies for pre-emption, in particular bilateral total adrenalectomy (Lips et al. 1981) and 4-gland parathyroidectomy with or without autografting of parathyroid slivers to the sternocleidomastoid muscle or the brachioradial muscle of the nondominant forearm (Yoshida et al. 2009, Moley et al. 2015).

Twenty-five years after the advent of the genomic epoch for MEN2, it may be pertinent to take stock of the wealth of genomic and outcome data accrued. This review article endeavors to gauge mutation-specific risks of tumor development in MEN2-associated glands over time against the sequelae of organ loss vs tumor recurrence in remnant glands with a view of striking a benefit–risk balance based on most current evidence from the international literature.

Evidence acquisition

Search strategy

An electronic MEDLINE search of the international literature was conducted with a cutoff of May 31, 2017 using key words that included the terms ‘medullary thyroid cancer/carcinoma’, ‘pheochromocytoma’, ‘hyperparathyroidism’, ‘hypercalcemia’, ‘multiple endocrine neoplasia type 2’ or ‘MEN2’, ‘thyroidectomy’, ‘adrenalectomy’, ‘parathyroidectomy’, ‘recurrence’ or ‘recurrent’, ‘steroid dependency’, ‘Addison’s disease’ or ‘Addisonian crisis’, ‘recurrent laryngeal nerve palsy’ or ‘vocal cord palsy’, ‘hypoparathyroidism’ and ‘hypocalcemia’.

The terms of this literature search were identified in the title, abstract or medical subject heading. Mere review articles were excluded from review. To avoid duplication, earlier reports from groups that updated previously published information in a subsequent, more comprehensive report were not considered. Pertinent publications were reviewed further, and data elements were extracted as appropriate in structured format.

Case definitions of MEN2 components

A diagnosis of medullary thyroid carcinoma typically required tumor extension beyond the basement membrane, demonstration of lymphatic or vascular invasion or both.

Pheochromocytoma typically was diagnosed in the presence of raised plasma-free metanephrines and normetanephrines, or 24-h urine metanephrines and normetanephrines, supported by histopathological confirmation of the biochemical diagnosis on the adrenal specimens.

A diagnosis of primary hyperparathyroidism was based on the evidence of hypercalcemia, typically in the presence of increased parathyroid hormone levels.

Results

Transformation from cellular hyperplasia to neoplasia

The RET proto-oncogene encodes for a transmembrane tyrosine kinase receptor expressed mainly in neuroendocrine cells from the neural crest. The constitutive activation of the mutated RET receptor protein is thought to give rise to hyperplasia of parafollicular C-cells, adrenal medullary cells and parathyroid chief cells. A second mutation in one of these neuroendocrine cells (‘second hit’) is thought to cause MTC (C-cell cancer), pheochromocytoma or primary hyperparathyroidism due to multiple hyperplastic nodules in a pattern best defined as pseudonodular parathyroid hyperplasia. Because acquisition of somatic mutations by these cells reflects the play of chance, the development of the different MEN2 components varies even among members of the same family, compromising predictions by which age the various MEN2 components may become clinically apparent (Machens et al. 2009b, Wells et al. 2013). As a corollary, the weaker is the transforming activity of inherited RET mutations (genotype), the less complete tends to be the penetrance of the other MEN2-associated components (phenotype).

Transformation of the thyroid gland

Progression from C-cell hyperplasia to early medullary thyroid cancer

Table 1 illustrates the age-related progression from C-cell hyperplasia to early MTC, with steep gradients among highest risk (ATA category HST), high-risk (ATA category H) and moderate-risk (ATA category MOD) RET mutations. The lead time provided by early identification of asymptomatic infants and young children as RET carriers delimits a ‘window of opportunity’, within which total thyroidectomy alone represents adequate therapy:

Table 1

Age-related penetrance of medullary thyroid cancer in children with RET mutations (literature review).

Children with medullary thyroid cancer,n (%)Biochemical cure,n (%)
Age at thyroidectomy, year
ATA 2015 categoryMutation in codonReference≤34–67–1213–18TotalTotal
HST (highest)918Brauckhoff et al. (2014)6 of 7 (86)2 of 2 (100)N/AN/A8 of 9 (88)9 of 9 (100)
Elisei et al. (2012)2 of 2 (100)a1 of 1 (100)a3 of 3 (100)0 of 3 (0)
H (high)634Elisei et al. (2012)1 of 1 (100)3 of 3 (100)3 of 3 (100)b7 of 7 (100)7 of 7 (100)
Skinner et al. (2005)6 of 9 (66)8 of 8 (100)1 of 1 (100)15 of 18 (83)16 of 18 (89)
MOD (moderate)609–620Skinner et al. (2005)0 of 1 (0)1 of 7 (14)4 of 8 (50)10 of 13 (77)15 of 29 (52)26 of 29 (90)
609Skinner et al. (2005)1 of 3 (33)1 of 3 (33)3 of 3 (100)
611Skinner et al. (2005)1 of 1 (100)1 of 1 (100)1 of 1 (100)
618Skinner et al. (2005)0 of 2 (0)2 of 4 (50)4 of 4 (100)b6 of 10 (60)9 of 10 (90%)
620Skinner et al. (2005)0 of 1 (0)1 of 5 (20)2 of 4 (50)4 of 5 (80)c7 of 15 (47)13 of 15 (87)

ATA, American Thyroid Association; RET, rearranged during transfection.

Node-positive children aged 8, 12, and 14 years.

Node-positive child aged 11 years.

Node-positive child aged 10 years.

  • For carriers of highest risk mutations (ATA category HST, notably M918T; classic MEN2B), surgical cure is achievable in expert hands before the age of four years but becomes exceptional thereafter (Elisei et al. 2012, Brauckhoff et al. 2014).
  • For carriers of high- and moderate-risk mutations (ATA categories H and MOD; classic and atypical MEN2A), nodal spread is very rarely present before the age of 10 years (Skinner et al. 2005, Elisei et al. 2012, Wells et al. 2015).

Depending on the location of a moderate-risk mutation on the RET receptor (Fig. 1), there are further, though clinically more subtle codon-specific differences: earlier progression to MTC when the mutation lodges in the extracellular cysteine-rich domain, especially in close proximity to the cell membrane (Machens et al. 2009a), as compared to a position in one of the intracellular tyrosine kinase domains (Rich et al. 2014).

The thyroid gland is more expendable than the adrenal or parathyroid glands, rendering pre-emptive thyroidectomy a more viable strategy than bilateral total adrenalectomy or 4-gland parathyroidectomy.

Biochemical window of opportunity: pre-emptive thyroidectomy

There is good evidence to suggest that MTC has not developed as long as basal calcitonin serum levels remain within normal limits (Machens et al. 2009c, Elisei et al. 2012). When these levels begin exceeding the upper normal limit of the calcitonin assay, usually <10 pg/mL for children aged 2 years and older (Castagna et al. 2015), the point of malignant transformation is coming closer. In the presence of basal calcitonin serum levels ≤30 pg/mL, node metastases have not been reported (Rohmer et al. 2011). If this biochemical ‘window of opportunity’ has been missed and neck nodes need to be dissected at incremental operative morbidity, chances of immediate biochemical cure become slimmer: only 57–31% with 1–10 node metastases, and a mere 0–4% with >10 node metastases (Machens et al. 2000, Scollo et al. 2003).

Complications by the child’s age at thyroidectomy and central node dissection

Table 2 depicts the incidence of complications, after thyroidectomy without and with central node dissection, stratified by the child’s age (Kluijfhout et al. 2015, Machens et al. 2016). Addition of central node dissection seems to raise the frequency of transient and permanent hypoparathyroidism, and more subtly, the frequency of transient recurrent laryngeal nerve palsy (Machens et al. 2016). The latter finding may reflect space constraints in the neck of children aged 3 years and younger whose recurrent laryngeal nerves may be less resilient to traction and hyperthermia from electrocoagulation. In line with the concept of greater vulnerability of infants, children younger than 3 years of age developed more often transient and permanent hypoparathyroidism, in particular when postoperative hypoparathyroidism was more prevalent overall (Table 2). To diminish operative morbidity, it may be prudent to use optical magnification, bipolar forceps coagulation and nerve-monitoring devices and preserve parathyroid glands in situ as much as possible.

Table 2

Age-related incidence of complications after thyroidectomy in children (literature review).

Children with complication after total thyroidectomy,n (%)
Age at thyroidectomy, year
ComplicationCentral node dissectionReference≤3<33–64–67–12 13–18>6
Transient RLN palsyNot performedKluijfhout et al. (2015)1 of 9 (11)0 of 15 (0)N/AN/A1 of 20 (5)
Not performedMachens et al. (2016)0 of 25 (0)0 of 39 (0)0 of 24 (0)0 of 11 (0)0 of 35 (0)
PerformedMachens et al. (2016)2 of 12 (17)0 of 21 (0)2 of 43 (5)4 of 55 (7)6 of 98 (6)
Permanent RLN palsyNot performedKluijfhout et al. (2015)1 of 9 (11)0 of 15 (0)N/AN/A0 of 20 (0)
Not performedMachens et al. (2016)0 of 25 (0)0 of 39 (0)0 of 24 (0)0 of 11 (0) 0 of 35 (0)
PerformedMachens et al. (2016)0 of 12 (0)0 of 21 (0) 0 of 43 (0)0 of 55 (0)0 of 98 (0)
Transient hypoparathyroidismNot performedKluijfhout et al. (2015)6 of 9 (67)7 of 15 (47)N/AN/A8 of 20 (40)
Not performedMachens et al. (2016)1 of 25 (4)3 of 39 (8) 3 of 24 (13)4 of 11 (36)7 of 35 (20)
PerformedMachens et al. (2016)0 of 12 (0)3 of 21 (14)19 of 43 (44)22 of 55 (40)41 of 98 (42)
Permanent hypoparathyroidismNot performedKluijfhout et al. (2015)2 of 9 (22)2 of 15 (13)N/AN/A5 of 20 (25)
Not performedMachens et al. (2016)0 of 25 (0)0 of 39 (0)0 of 24 (0)0 of 11 (0)0 of 35 (0)
PerformedMachens et al. (2016)0 of 12 (0)1 of 21 (5) 5 of 43 (12)7 of 55 (13)12 of 98 (12)

N/A, not available.

Transformation of the adrenal glands

Age-related penetrance of adrenal pheochromocytoma

Pheochromocytomas in MEN2 have more of an adrenal phenotype secondary to predominant epinephrine production from the adrenal tumor. Extraadrenal pheochromocytoma and adrenal ganglioneuroma in MEN2 are exceptional (Lora et al. 2005).

Table 3 summarizes the literature on the penetrance of MEN2-associated pheochromocytoma:

Table 3

Age-related penetrance of pheochromocytoma in MEN2 (literature review).

Pheochromocytoma
ATA 2015 categoryMutation in codonReferencePenetrance overall, n (%)Age at first diagnosis, year, meanUnilateral penetrance, n %Bilateral penetrance, n (%)
HST (highest)918Machens et al. (2013a)10 of 37 (27)25.54 of 37 (11)6 of 37 (16)
H (high)634Asari et al. (2006)N/AN/A16a
Rodriguez et al. (2008)52 of 161 (32.3)36.4–38.126 of 161 (16.1)26 of 161 (16.1)
Machens et al. (2013a)51 of 170 (30.0)34.719 of 170 (11.2)32 of 170 (18.8)
MOD (moderate)609–620Asari et al. (2006)N/AN/A44b
609–630
Frank-Raue et al. (2011)54 of 319 (16.9)42 (median) 39 of 319 (12.2)15 of 319 (4.7)
Machens et al. (2013a)19 of 112 (17.0)40.515 of 112 (13.4)4 of 112 (3.6)
768–891Asari et al. (2006)N/AN/A20
Machens et al. (2013a)4 of 155 (2.6)56.54 of 155 (2.6)0 of 155 (0)

Bilateral pheochromocytomas were metachronous in 2 (33%) and synchronous in 4 (67%) of all 6 children with bilateral pheochromocytoma; bBilateral pheochromocytomas were metachronous in 3 (75%) and synchronous in 1 (25%) of all 4 children with bilateral pheochromocytoma.

ATA, American Thyroid Association.

  • Highest and high-risk mutations (ATA categories HST and H; classic MEN2B and classic MEN2A) carried comparable risks of pheochromocytoma in the order of 27–32.3% around the age of 26 and 35 years, respectively (Asari et al. 2006, Rodriguez et al. 2008, Machens et al. 2013a). These pheochromocytomas involved both adrenals in 50–60%, two-thirds synchronously and one-third metachronously.
  • Moderate-risk mutations (ATA category MOD; atypical MEN2A) entailed much lower risks of pheochromocytoma in the order of 17% by the early 40s for mutations in cysteine codons 609–620/630, and 2.6% by the age of 56.5 years for mutations in non-cysteine codons 768–891 (Asari et al. 2006, Frank-Raue et al. 2011, Machens et al. 2013a). Three-quarters of these pheochromocytomas were unilateral only.

In children carrying the highest and high-risk mutations (ATA categories HST and H), screening for pheochromocytoma generally is recommended to start at 8 years of age (Rowland et al. 2013, Wells et al. 2015), and for moderate-risk mutations (ATA category MOD) after 15 years of age (Machens et al. 2013a, Wells et al. 2015). To determine personal lifetime risks of pheochromocytoma, it is more worthwhile to evaluate mutation-specific risks by age (in 10–20 year increments), rather than referring to summary data. That level of detail is rarely available for ATA risk categories. Exceptions include moderate-risk mutations in exon 10 (ATA category MOD; mutations in cysteine codons 609–620), in which the penetrance of pheochromocytoma was 0% by age 10 years; 0.8% by age 20 years; 5.1% by age 30 years, 12.0% by age 40 years; 23.1% by age 50 years and 33.2% by age 60 years (Frank-Raue et al. 2011).

For such long-term observation, patient compliance with follow-up over decades is imperative.

Because adrenal mortality has been reported almost exclusively in connection with big pheochromocytomas (Dralle et al. 1992), there is evidence to suggest that continual biochemical screening may spot pheochromocytoma before it gives rise to adrenergic crisis.

Subtotal vs total adrenalectomy: risk of recurrence vs steroid dependence

Owing to the infrequency of pheochromocytoma, there is a paucity of data about the mutation-specific risk of developing a second pheochromocytoma:

  • Ipsilaterally after unilateral–subtotal adrenalectomy inside the adrenal remnant, and
  • Contralaterally without or after contralateral–subtotal adrenalectomy

The risk of developing a second pheochromocytoma inside an adrenal remnant, by implication, should be no greater, or perhaps even lower, than the risk of developing the first pheochromocytoma in an entire adrenal gland. In keeping (Table 4), a second pheochromocytoma rarely originates from an adrenal remnant ipsilaterally (0–14%) and more often from an intact adrenal gland contralaterally (43–57%) (Lairmore et al. 1993, Scholten et al. 2011, Castinetti et al. 2014).

Table 4

Unilateral and contralateral adrenal recurrence after initial adrenalectomy in MEN type 2 (literature review).

Adrenal recurrence after initial adrenalectomySteroid dependency
UnilateralContralateral
Initial adrenalectomyReferencePatients, n (%)Time to event, year, median (range)Patients, n (%)Time to event, year, median (range)Patients, n (%)Follow-up, year, median (range)
UnilateralSubtotalScholten et al. (2011)1 of 7 (14)N/A4 of 7 (57)[6.3 (1.8–9.7)]0 of 7 (0)15.8 (1.2–31.9)
TotalLairmore et al. (1993)0 of 23 (0)[9.4 (0.7–28.5)]**12 of 23 (52)11.9 (0.4–21.2)**0 of 23 (0)9.4 (0.7–28.5)**
Scholten et al. (2011)0 of 30 (0)[5.5 (0.1–38.6)]13 of 30 (43)[8.5 (0.5–19.9)]0 of 30 (0)11.5 (0.1–41.8)
Bilateral SubtotalScholten et al. (2011)2 of 2 (100)7.1 (4.1–10.2)0 of 2 (0)7.2 (4.1–10.2)0 of 2 (0)14.5 (12.8–16.3)
TotalLairmore et al. (1993)0 of 32 (0)0 of 32 (0)***
Scholten et al. (2011)1 of 22 (5)34.10 of 22 (0)23.0 (0.1–34.1)22 of 22 (100)23.0 (0.1–35.2)
AnySubtotalCastinetti et al. (2014)4 of 114 (4)9.5 (6–13)N/A10** (1–28)
TotalCastinetti et al. (2014)11 of 438 (3)14.2** (1–23)N/A13** (1–40)
BilateralSubtotal*Castinetti et al. (2014)N/A35 of 82 (43)
AnyCastinetti et al. (2014)N/A292 of 339 (86)

Numbers in squared brackets indicate approximations.

Scholten et al. 2011: ≥75% ATA H mutations.

Castinetti et al. (2014): 5% ATA HST mutations; 84% ATA H mutations; 11% ATA MOD mutations.

*One or both adrenals; **Mean; ***10 of 43 (23%) patients experienced at least one episode of adrenal insufficiency/Addisonian crisis (fatal in one patient).

Before the turn of the century, bilateral total adrenalectomy used to be the gold standard approach to the adrenal glands in MEN2 because of

  • Histopathological demonstration that both adrenal glands were riddled with adrenal medullary hyperplasia (Lips et al. 1978).
  • A perceived high probability of developing a second pheochromocytoma (Lairmore et al. 1993).
  • Reports of MEN2 families affected by multiple fatal cardiovascular and cerebrovascular events attributable to adrenergic crisis from occult pheochromocytoma (Lips et al. 1981).
  • Lingering concerns about malignancy because initial estimates of developing malignant pheochromocytoma exceeded current risk estimates of ≤1%, perhaps due to initial ‘publication bias’.

Only gradually appreciated were the adverse consequences of bilateral total adrenalectomy, tipping the balance away from total adrenalectomy:

The limited risk of recurrence for adrenal remnants (Table 4) and the availability of tissue-sparing surgical technology made subtotal adrenalectomy – attuned to the extent of the adrenal tumor – the surgical intervention of choice for pheochromocytoma (Dralle et al. 1992, Lairmore et al. 1993, Brauckhoff et al. 2003, Asari et al. 2006, Scholten et al. 2011, Machens et al. 2013a, Wells et al. 2015). Rare exceptions include technical unfeasibility of subtotal adrenalectomy when the adrenal tumor occupies most or all of the adrenal gland.

Accurately determining residual adrenal volume, in which ‘recurrent’ pheochromocytoma may develop, has come as a challenge. Three-dimensional reconstruction on computed tomography overestimates residual adrenal volume. In fact, the posterior extension of an adrenal remnant cannot be precisely measured without mobilization, which would jeopardize its blood supply (Brauckhoff et al. 2008). In the absence of more precise measurements, residual adrenal volume continues to be put in proportion to the volume of the entire adrenal gland before resection. These intraoperative estimates suggest that preservation of one-third of the adrenal gland offers adrenal stress capacity sufficient to obviate the need for corticosteroid supplementation (Brauckhoff et al. 2003). Even after bilateral subtotal adrenalectomy, loss of 70–85% of adrenal tissue can be compensated for by the adrenal remnants, although some subclinical compromise commonly remains (Wells et al. 2015).

Transformation of the parathyroid glands

Age-related penetrance of primary hyperparathyroidism

The risk of parathyroid disease is genetically determined and not a response to elevated calcitonin serum levels (Dralle et al. 1992).

Table 5 provides information on the penetrance of MEN2-associated primary hyperparathyroidism, typically caused by no more than one enlarged parathyroid gland:

Table 5

Age-related penetrance of primary hyperparathyroidism in MEN2 (literature review).

Primary hyperparathyroidism
ATA 2015 categoryMutation in codonReferencePenetrance, n(%)Age at first diagnosis, year, mean
HST (highest)918
H (high)634Asari et al. (2006)3 of 7 (43)(42.6–49.0)*
Schuffenecker et al. (1998)36 of 188 (19.1)33.7
Machens et al. (2013a)16 of 170 (9.4)39.7
MOD (moderate)609–620Asari et al. (2006)0 of 8 (0)(42.6–49.0)*
Frank-Raue et al. (2011)8 of 299 (2.7)46 (median)
609–620 (609–630)
Machens et al. (2013a)2 of 112 (1.8)38.5
768Asari et al. (2006)0 of 2 (0)(42.6–49.0)*
–891
Machens et al. (2013a)2 of 155 (1.3)54.5

ATA, American Thyroid Association.

*Whole study population.

  • Highest risk mutations (ATA category HST; classic MEN2B) do not produce primary hyperparathyroidism.
  • High-risk mutations (ATA category H; classic MEN2A) entail a risk of primary hyperparathyroidism of 9.4% by the age of 40 years using institutional data (Machens et al. 2013a). This risk was estimated twice as high (19.1% by age 34 years) based on the data from a national MEN2 registry going back to 1984 (Schuffenecker et al. 1998) or more than fourfold greater in an earlier institutional series (Asari et al. 2006). The penetrance of primary hyperparathyroidism was rated using these MEN2 registry data at 14% by age 30 years; 26% by age 40 years; 48% by age 60 years and 81% by age 70 years (Schuffenecker et al. 1998).
  • Moderate-risk mutations (ATA category MOD; atypical MEN2A) infrequently go along with primary hyperparathyroidism (Asari et al. 2006, Frank-Raue et al. 2011, Machens et al. 2013a). Current estimates range from 1.3% by the age of 54.5 years (mutations in non-cysteine codons 768–891) to 2.7% by the age of 46 years (mutations in cysteine codons 609–620 in exon 10). The penetrance of primary hyperparathyroidism, pooling data of 27 centers from 15 countries, was estimated at 0% by age 20 years; 0.5% by age 30 years, 1.8% by age 40 years; 3.9% by age 50 years and 3.9% by age 60 years (Frank-Raue et al. 2011).

For high-risk mutations (ATA category H), screening for primary hyperparathyroidism usually is advocated to begin after 10 years of age, and for moderate-risk mutations (ATA category MOD), after 15 years of age (Machens et al. 2013a, Wells et al. 2015).

Limited vs total parathyroidectomy: risk of recurrence vs permanent postoperative hypoparathyroidism

Because primary hyperparathyroidism in MEN2 almost always is mild and benign, removing only enlarged parathyroid glands is adequate most of the time (Dralle et al. 1992, Wells et al. 2015). The adequacy of parathyroidectomy is judged intraoperatively by the prompt fall of the intact parathyroid hormone levels by 50% and more. As a matter of principle, normal parathyroid glands should be preserved in situ on a vascular pedicle.

The risk of recurrent primary hyperparathyroidism, arising from the transformation of one of three or fewer remaining parathyroid gland, by implication, should be less than the initial risk of primary hyperparathyroidism for all four parathyroid glands:

  • For high-risk mutations (ATA category H; classic MEN2A), the risk of recurrence should be modest (≤19.1%).
  • For moderate-risk mutations (ATA category MOD; atypical MEN2A), the risk of recurrence should be negligible (≤2.7%).

Although frequently used before the millennium, total parathyroidectomy with autotransplantation of parathyroid slivers to the nondominant forearm or the neck has been abandoned because of its attendant 6–9% risk of permanent hypoparathyroidism. That risk compares unfavorably with the 1–4% risk attendant to in situ preservation of the parathyroid glands (Dralle et al. 1998, Moley et al. 2015).

Discussion

The advent of sensitive calcitonin, catecholamine and parathyroid hormone assays and DNA-based screening programs changed the landscape for MEN2 (Graze et al. 1978, Gagel et al. 1988, Machens et al. 2013a, Machens & Dralle 2015). Biochemical (i.e., calcitonin) screening was shown to be more sensitive than anatomical screening (i.e., neck ultrasonography) for microscopic disease (i.e., MTC) in asymptomatic children at risk of MEN2A (Morris et al. 2013). At inception, calcitonin screening was largely cross-sectional, encompassing gene carriers at various stages of tumor development. With the increasing inclusion of asymptomatic infants and young children, the focus of screening programs shifted toward longitudinal observation of family members at risk of developing MEN2 tumors. This yielded an unprecedented opportunity to monitor individuals at risk of developing MEN2 over decades and to learn more about the molecular epidemiology of the various mutations underlying MEN2 (Machens et al. 2013b).

Paradigm shift from the removal of target organs to targeted surgical intervention

The important insight into the natural evolution of MEN2 gained over the past 25 years (i.e., one generation) changed the scene for the management of MEN2 in the new millenium: from removing target organs early in the course, at the expense of greater operative morbidity, to enabling better quality of life under close biochemical surveillance, with targeted (‘tissue-sparing’) resection of adrenal tumors and hyperplastic parathyroid glands. This progress has rendered prophylactic removal of organs for asymptomatic benign lesions rarely, if ever, acceptable in a well-organized society.

In the genomic era, the natural course of the disease is interfered with ideally as soon as the upper normal limit of the respective organ-specific assay has been exceeded (Machens et al. 2009c, Elisei et al. 2012) and a valid adrenal and parathyroid surgical target has been identified (Machens et al. 2013a), respectively:

  • Pre-emptive total thyroidectomy, circumventing incremental operative morbidity associated with central node dissection in the neck (Machens et al. 2009c, Machens et al. 2016);
  • Subtotal adrenalectomy attuned to the adrenal tumor(s), trading a grave risk of steroid dependency and Addisonian crisis for a smaller risk of developing a second pheochromocytoma inside an adrenal remnant (Brauckhoff et al. 2003);
  • Parathyroidectomy of enlarged glands only, trading a 6% risk of postoperative hypoparathyroidism (Moley et al. 2015) for a smaller risk of developing another parathyroid tumor (‘recurrent’ hyperparathyroidism).

This paradigm shift, consisting in weighing mutation-specific risks of tumor development against the sequelae of organ loss and the risk of developing additional tumors inside remnant organs during informed consent, falls within the realms of personalized medicine and value-based decision making. Value-based decisions always have a personal component and require clinician and patient to take personal responsibility.

Population-based effectiveness of DNA-based screening for MEN2

In countries like Germany where health care systems cover the analysis of all relevant RET mutations, the effectiveness of DNA-based screening for control of MTC at the population level has been impressive (Machens & Dralle 2015):

For high-risk mutations (ATA category H; ‘classic’ MEN2A), a decline since 1963 in the percentage of:

  • Index patients among all carriers from 50 to 16%;
  • MTC among non-index patients from 100 to 28%;
  • Node-positive MTC from 100 to 0%;

whereas biochemical cure increased from 0 to 100%.

For moderate-risk mutations (ATA category MOD; ‘incomplete’ MEN2A), a fall since 1995 in the percentage of:

  • Index patients among all carriers from 100% to 29–31%
  • MTC among non-index patients from 48–81% to 19–60%;
  • Node-positive MTC from 67 to 33% (cysteine codons 609–630) and 11 to 10% (non-cysteine codons 768–891),

whereas biochemical cure increased from 71 to 78% (cysteine codons 609–630) and 95–100% (non-cysteine codons 768–891).

Based on data from the French MEN2 registry, 5.6–9.1% of germline mutations (running in 8–13 of 143 families) occur de novo in the parental germline (Schuffenecker et al. 1997), replenishing the pool of index patients that screening programs seek to deplete. These countervailing effects may make it unfeasible to diminish the percentage of index patients below the spontaneous mutation rate of 5.6–9.1%.

Future perspectives

Twenty-five years into the molecular era, correlations between genotype (mutations in RET codons 609, 611, 618, 620, 630, 634, 768, 790, 804, 891 and 918) and phenotype (MTC, pheochromocytoma, hyperplastic parathyroid glands) are well established at the population level, allowing clinicians to practice the law of averages and/or worst-case scenarios. These mutational profiles provide for a genetic framework within which transformation from cellular hyperplasia to neoplasia unfolds at a variable pace.

Predicting this cellular transformation precisely in terms of time (age at onset) and space (affected glands) at the individual level has proved elusive. This is why screening for cellular biomarkers with sensitive calcitonin, catecholamine and parathyroid hormone assays has been gathering momentum since the millennium. These biochemical screening programs strive to open a surgical ‘window of opportunity’ by detecting:

Within this ‘window of opportunity’, the extent of the operation, its attendant morbidity and the resultant organ loss, with its risk of steroid and/or calcium/vitamin D dependency, can be kept low.

Because patient age confounds genotype–phenotype correlations, future research in MEN2 should be directed at delineating further the mutation-specific, age-dependent penetrance of pheochromocytoma and primary hyperparathyroidism in older adults carrying the trait. Far longer follow-up periods, encompassing several decades, will be necessary to accrue more adrenal and parathyroid events. Larger event rates would help refine the current risk-oriented approach to MEN2 and foster wider dissemination of Bayesian inference considering the proband’s age at the time of assessment (Ponder et al. 1988) in addition to mutational risk.

More research is warranted into the risk of developing secondary pheochromocytoma in adrenal remnants or intact glands, taking the adrenal volume at risk into account. Furthermore, survival data will increasingly need to be fit into the benefit–risk equation (Grubbs & Gagel 2015).

The sweeping changes in the management of MEN2 since the new millenium hold the hope that death and major morbidity from this uncommon disease can be eliminated in our lifetime.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

References

  • Asari R, Scheuba C, Kaczirek K & Niederle B 2006 Estimated risk of pheochromocytoma recurrence after adrenal-sparing surgery in patients with multiple endocrine neoplasia type 2A. Archives of Surgery 141 11991205. (https://doi.org/10.1001/archsurg.141.12.1199)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Berndt I, Reuter M, Saller B, Frank-Raue K, Groth P, Grussendorf M, Raue F, Ritter MM & Höppner W 1998 A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. Journal of Clinical Endocrinology and Metabolism 83 770774. (https://doi.org/10.1210/jcem.83.3.4619)

    • Search Google Scholar
    • Export Citation
  • Bolino A, Schuffenecker I, Luo Y, Seri M, Silengo M, Tocco T, Chabrier G, Houdent C, Murat A, Schlumberger M, et al. 1995 RET mutations in exons 13 and 14 of FMTC patients. Oncogene 10 24152419.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Brauckhoff M, Gimm O, Thanh PN, Bär A, Ukkat J, Brauckhoff K, Bönsch T & Dralle H 2003 Critical size of residual adrenal tissue and recovery from impaired early postoperative adrenocortical function after subtotal bilateral adrenalectomy. Surgery 134 10201027. (https://doi.org/10.1016/j.surg.2003.08.005)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Brauckhoff M, Stock K, Stock S, Lorenz K, Sekulla C, Brauckhoff K, Thanh PN, Gimm O, Spielmann RP & Dralle H 2008 Limitations of intraoperative adrenal remnant volume measurement in patients undergoing subtotal adrenalectomy. World Journal of Surgery 32 863872. (https://doi.org/10.1007/s00268-007-9402-y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Brauckhoff M, Machens A, Lorenz K, Bjøro T, Varhaug JE & Dralle H 2014 Surgical curability of medullary thyroid cancer in multiple endocrine neoplasia 2B: a changing perspective. Annals of Surgery 259 800806. (https://doi.org/10.1097/SLA.0b013e3182a6f43a)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Castagna MG, Fugazzola L, Maino F, Covelli D, Memmo S, Sestini F, Fioravanti C, Ferraris Fusarini C, Scapellato C, Macchini F, et al. 2015 Reference range of serum calcitonin in pediatric population. Journal of Clinical Endocrinology and Metabolism 100 17801784. (https://doi.org/10.1210/jc.2014-4508)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Castinetti F, Qi XP, Walz MK, Maia AL, Sansó G, Peczkowska M, Hasse-Lazar K, Links TP, Dvorakova S, Toledo RA, et al. 2014 Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associated with multiple endocrine neoplasia type 2: an international retrospective population-based study. Lancet Oncology 15 648655. (https://doi.org/10.1016/S1470-2045(14)70154-8)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P & Wells SA Jr 1993 Mutations in the RET proto-oncogene are associated with MEN2A and FMTC. Human Molecular Genetics 2 851856. (https://doi.org/10.1093/hmg/2.7.851)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dralle H, Scheumann GF, Kotzerke J & Brabant EG 1992 Surgical management of MEN2. Recent Results in Cancer Research 125 167195.

  • Dralle H, Gimm O, Simon D, Frank-Raue K, Görtz G, Niederle B, Wahl RA, Koch B, Walgenbach S, Hampel R, 1998 Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma: German and Austrian experience. World Journal of Surgery 22 744750. (https://doi.org/10.1007/s002689900463)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Elisei R, Romei C, Renzini G, Bottici V, Cosci B, Molinaro E, Agate L, Cappagli V, Miccoli P, Berti P, 2012 The timing of total thyroidectomy in RET gene mutation carriers could be personalized and safely planned on the basis of serum calcitonin: 18 years experience at one single center. Journal of Clinical Endocrinology and Metabolism 97 426435. (https://doi.org/10.1210/jc.2011-2046)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Eng C, Smith DP, Mulligan LM, Healey CS, Zvelebil MJ, Stonehouse TJ, Ponder MA, Jackson CE, Waterfield MD & Ponder BA 1995 A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. Oncogene 10 509513.

    • Search Google Scholar
    • Export Citation
  • Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Amstel HK, Lips CJ, Nishisho I, Takai SI, et al. 1996 The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. Journal of the American Medical Association 276 15751579. (https://doi.org/10.1001/jama.1996.03540190047028)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Frank-Raue K, Rondot S & Raue F 2010 Molecular genetics and phenomics of RET mutations: impact on prognosis of MTC. Molecular and Cellular Endocrinology 322 27. (https://doi.org/10.1016/j.mce.2010.01.012)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Frank-Raue K, Rybicki LA, Erlic Z, Schweizer H, Winter A, Milos I, Toledo SP, Toledo RA, Tavares MR, Alevizaki M, 2011 International RET Exon 10 Consortium. Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. Human Mutation 32 5158. (https://doi.org/10.1002/humu.21385)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gagel RF, Tashjian AH, Cummings T, Papathanasopoulos N, Kaplan MM, DeLellis RA, Wolfe HJ & Reichlin S 1988 The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. New England Journal of Medicine 318 478484. (https://doi.org/10.1056/NEJM198802253180804)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Graze K, Spiler IJ, Tashjian AH, Melvin KE, Cervi-Skinner S, Gagel RF, Miller HH, Wolfe HJ, DeLellis RA, Leape L, et al. 1978 Natural history of familial medullary thyroid carcinoma. Effect of a program for early diagnosis. New England Journal of Medicine 299 980985. (https://doi.org/10.1056/NEJM197811022991804)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Grubbs EG & Gagel RF 2015 My, how things have changed in multiple endocrine neoplasia type 2A! Journal of Clinical Endocrinology and Metabolism 100 25322535. (https://doi.org/10.1210/jc.2015-2516)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Hofstra RM, Fattoruso O, Quadro L, Wu Y, Libroia A, Verga U, Colantuoni V & Buys CH 1997 A novel point mutation in the intracellular domain of the ret protooncogene in a family with medullary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 82 41764178. (https://doi.org/10.1210/jcem.82.12.4439)

    • Search Google Scholar
    • Export Citation
  • Kluijfhout WP, van Beek DJ, Verrijn Stuart AA, Lodewijk L, Valk GD, van der Zee DC, Vriens MR & Borel Rinkes IH 2015 Postoperative complications after prophylactic thyroidectomy for very young patients with multiple endocrine neoplasia type 2: retrospective cohort analysis. Medicine 94 e1108. (https://doi.org/10.1097/MD.0000000000001108)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lairmore TC, Ball DW, Baylin SB & Wells SA Jr 1993 Management of pheochromocytomas in patients with multiple endocrine neoplasia type 2 syndromes. Annals of Surgery 217 595601. (https://doi.org/10.1097/00000658-199306000-00001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Learoyd DL, Marsh DJ, Richardson AL, Twigg SM, Delbridge L & Robinson BG 1997 Genetic testing for familial cancer. Consequences of RET proto-oncogene mutation analysis in multiple endocrine neoplasia, type 2. Archives of Surgery 132 10221025. (https://doi.org/10.1001/archsurg.1997.01430330088015)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lips CJ, Minder WH, Leo JR, Alleman A & Hackeng WH 1978 Evidence of multicentric origin of the multiple endocrine neoplasia syndrome type 2a (Sipple's syndrome) in a large family in the Netherlands. Diagnostic and therapeutic implications. American Journal of Medicine 64 569578. (https://doi.org/10.1016/0002-9343(78)90575-2)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lips KJ, Van der Sluys Veer J, Struyvenberg A, Alleman A, Leo JR, Wittebol P, Minder WH, Kooiker CJ, Geerdink RA, Van Waes PF, et al. 1981 Bilateral occurrence of pheochromocytoma in patients with the multiple endocrine neoplasia syndrome type 2A (Sipple’s syndrome). American Journal of Medicine 70 10511060. (https://doi.org/10.1016/0002-9343(81)90866-4)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lips CJ, Landsvater RM, Höppener JW, Geerdink RA, Blijham G, van Veen JM, van Gils AP, de Wit MJ, Zewald RA, Berends MJ, et al. 1994 Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. New England Journal of Medicine 331 828835. (https://doi.org/10.1056/NEJM199409293311302)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lora MS, Waguespack SG, Moley JF & Walvoord EC 2005 Adrenal ganglioneuromas in children with multiple endocrine neoplasia type 2: a report of two cases. Journal of Clinical Endocrinology and Metabolism 90 43834387. (https://doi.org/10.1210/jc.2004-2526)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Machens A, Gimm O, Ukkat J, Hinze R, Schneyer U & Dralle H 2000 Improved prediction of calcitonin normalization in medullary thyroid carcinoma patients by quantitative lymph node analysis. Cancer 88 19091915. (https://doi.org/10.1002/(SICI)1097-0142(20000415)88:8<1909::AID-CNCR21>3.0.CO;2-A)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Machens A, Niccoli-Sire P, Hoegel J, Frank-Raue K, van Vroonhoven TJ, Roeher HD, Wahl RA, Lamesch P, Raue F, Conte-Devolx B, et al. 2003 Early malignant progression of hereditary medullary thyroid cancer. New England Journal of Medicine 349 15171525. (https://doi.org/10.1056/NEJMoa012915)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Machens A, Hauptmann S & Dralle H 2009 a Modification of multiple endocrine neoplasia 2A phenotype by cell membrane proximity of RET mutations in exon 10. Endocrine Related Cancer 16 171177. (https://doi.org/10.1677/ERC-08-0096)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Machens A, Lorenz K & Dralle H 2009 b Constitutive RET tyrosine kinase activation in hereditary medullary thyroid cancer: clinical opportunities. Journal of Internal Medicine 266 114125. (https://doi.org/10.1111/j.1365-2796.2009.02113.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Machens A, Lorenz K & Dralle H 2009 c Individualization of lymph node dissection in RET (rearranged during transfection) carriers at risk for medullary thyroid cancer: value of pretherapeutic calcitonin levels. Annals of Surgery 250 305310. (https://doi.org/10.1097/SLA.0b013e3181ae333f)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Machens A, Lorenz K & Dralle H 2013 a Peak incidence of pheochromocytoma and primary hyperparathyroidism in multiple endocrine neoplasia 2: need for age-adjusted biochemical screening. Journal of Clinical Endocrinology and Metabolism 98 E336E345. (https://doi.org/10.1210/jc.2012-3192)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Machens A, Lorenz K, Sekulla C, Höppner W, Frank-Raue K, Raue F & Dralle H 2013 b Molecular epidemiology of multiple endocrine neoplasia 2: implications for RET screening in the new millenium. European Journal of Endocrinology 168 307314. (https://doi.org/10.1530/EJE-12-0919)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Machens A & Dralle H 2015 Therapeutic effectiveness of screening for multiple endocrine neoplasia type 2A. Journal of Clinical Endocrinology and Metabolism 100 25392545. (https://doi.org/10.1210/jc.2015-1689)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Machens A, Elwerr M, Thanh PN, Lorenz K, Schneider R & Dralle H 2016 Impact of central node dissection on postoperative morbidity in pediatric patients with suspected or proven thyroid cancer. Surgery 160 484492. (https://doi.org/10.1016/j.surg.2016.03.007)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Moley JF, Skinner M, Gillanders WE, Lairmore TC, Rowland KJ, Traugott AL, Jin LX & Wells SA Jr 2015 Management of the parathyroid glands during preventive thyroidectomy in patients with multiple endocrine neoplasia type 2. Annals of Surgery 262 641646. (https://doi.org/10.1097/SLA.0000000000001464)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Morris LF, Waguespack SG, Edeiken-Monroe BS, Lee JE, Rich TA, Ying AK, Warneke CL, Evans DB, Perrier ND & Grubbs EG 2013 Ultrasonography should not guide the timing of thyroidectomy in pediatric patients diagnosed with multiple endocrine neoplasia syndrome 2A through genetic screening. Annals of Surgical Oncology 20 5359. (https://doi.org/10.1245/s10434-012-2589-7)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, et al. 1993 Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363 458460. (https://doi.org/10.1038/363458a0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ponder BA, Ponder MA, Coffey R, Pembrey ME, Gagel RF, Telenius-Berg M, Semple P & Easton DF 1988 Risk estimation and screening in families of patients with medullary thyroid carcinoma. Lancet 331 397401. (https://doi.org/10.1016/S0140-6736(88)91191-9)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Rich TA, Feng L, Busaidy N, Cote GJ, Gagel RF, Hu M, Jimenez C, Lee JE, Perrier N, Sherman SI, et al. 2014 Prevalence by age and predictors of medullary thyroid cancer in patients with lower risk germline RET proto-oncogene mutations. Thyroid 24 10961106. (https://doi.org/10.1089/thy.2013.0620)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rodriguez JM, Balsalobre M, Ponce JL, Ríos A, Torregrosa NM, Tebar J & Parrilla P 2008 Pheochromocytoma in MEN2A syndrome. Study of 54 patients. World Journal of Surgery 32 25202526. (https://doi.org/10.1007/s00268-008-9734-2)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rohmer V, Vidal-Trecan G, Bourdelot A, Niccoli P, Murat A, Wemeau JL, Borson-Chazot F, Schvartz C, Tabarin A, Chabre O, 2011 Prognostic factors of disease-free survival after thyroidectomy in 170 young patients with a RET germline mutation: a multicenter study of the Groupe Francais d’Etude des Tumeurs Endocrines. Journal of Clinical Endocrinology and Metabolism 96 E509E518. (https://doi.org/10.1210/jc.2010-1234)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Rowland KJ, Chernock RD & Moley JF 2013 Pheochromocytoma in an 8-year-old patient with multiple endocrine neoplasia type 2A: implications for screening. Journal of Surgical Oncology 108 203206. (https://doi.org/10.1002/jso.23378)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Scollo C, Baudin E, Travagli JP, Caillou B, Bellon N, Leboulleux S & Schlumberger M 2003 Rationale for central and bilateral lymph node dissection in sporadic and hereditary medullary thyroid cancer. Journal of Clinical Endocrinology and Metabolism 88 20702075. (https://doi.org/10.1210/jc.2002-021713)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Scholten A, Valk GD, Ulfman D, Borel Rinkes IH & Vriens MR 2011 Unilateral subtotal adrenalectomy for pheochromocytoma in multiple endocrine neoplasia type 2 patients: a feasible surgical strategy. Annals of Surgery 254 10221027. (https://doi.org/10.1097/SLA.0b013e318237480c)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Schuffenecker I, Ginet N, Goldgar D, Eng C, Chambe B, Boneu A, Houdent C, Pallo D, Schlumberger M, Thivolet C, 1997 Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. Le Groupe d’Etude des Tumeurs à Calcitonine. American Journal of Human Genetics 60 233237. (https://doi.org/10.1210/jcem.83.2.4529)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Schuffenecker I, Virally-Monod M, Brohet R, Goldgar D, Conte-Devolx B, Leclerc L, Chabre O, Boneu A, Caron J, Houdent C, 1998 Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Groupe d'Etude des Tumeurs à Calcitonine. Journal of Clinical Endocrinology and Metabolism 83 487491.

    • Search Google Scholar
    • Export Citation
  • Sipple JH 1961 The association of pheochromocytoma with carcinoma of the thyroid gland. American Journal of Medicine 31 163166. (https://doi.org/10.1016/0002-9343(61)90234-0)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Skinner MA, Moley JA, Dilley WG, Owzar K, DeBenedetti MK & Wells SA Jr 2005 Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. New England Journal of Medicine 353 11051113. (https://doi.org/10.1056/NEJMoa043999)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Wells SA Jr, Chi DD, Toshima K, Dehner LP, Coffin CM, Dowton SB, Ivanovich JL, DeBenedetti MK, Dilley WG, Moley JF, 1994 Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Annals of Surgery 220 237247. (https://doi.org/10.1097/00000658-199409000-00002)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wells SA Jr, Pacini F, Robinson BG & Santoro M 2013 Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. Journal of Clinical Endocrinology and Metabolism 98 31493164. (https://doi.org/10.1210/jc.2013-1204)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, Pacini F, et al. 2015 Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25 567610. (https://doi.org/10.1089/thy.2014.0335)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Williams ED 1965 A review of 17 cases of carcinoma of the thyroid and phaeochromocytoma. Journal of Clinical Pathology 18 288292. (https://doi.org/10.1136/jcp.18.3.288)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yoshida S, Imai T, Kikumori T, Wada M, Sawaki M, Takada H, Yamada T, Sato S, Sassa M, Uchida H, et al. 2009 Long term parathyroid function following total parathyroidectomy with autotransplantation in adult patients with MEN2A. Endocrine Journal 56 545551. (https://doi.org/10.1507/endocrj.K09E-005)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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    Prevalence of highest, high- and moderate-risk mutations in MEN2.

  • Asari R, Scheuba C, Kaczirek K & Niederle B 2006 Estimated risk of pheochromocytoma recurrence after adrenal-sparing surgery in patients with multiple endocrine neoplasia type 2A. Archives of Surgery 141 11991205. (https://doi.org/10.1001/archsurg.141.12.1199)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Berndt I, Reuter M, Saller B, Frank-Raue K, Groth P, Grussendorf M, Raue F, Ritter MM & Höppner W 1998 A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. Journal of Clinical Endocrinology and Metabolism 83 770774. (https://doi.org/10.1210/jcem.83.3.4619)

    • Search Google Scholar
    • Export Citation
  • Bolino A, Schuffenecker I, Luo Y, Seri M, Silengo M, Tocco T, Chabrier G, Houdent C, Murat A, Schlumberger M, et al. 1995 RET mutations in exons 13 and 14 of FMTC patients. Oncogene 10 24152419.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Brauckhoff M, Gimm O, Thanh PN, Bär A, Ukkat J, Brauckhoff K, Bönsch T & Dralle H 2003 Critical size of residual adrenal tissue and recovery from impaired early postoperative adrenocortical function after subtotal bilateral adrenalectomy. Surgery 134 10201027. (https://doi.org/10.1016/j.surg.2003.08.005)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Brauckhoff M, Stock K, Stock S, Lorenz K, Sekulla C, Brauckhoff K, Thanh PN, Gimm O, Spielmann RP & Dralle H 2008 Limitations of intraoperative adrenal remnant volume measurement in patients undergoing subtotal adrenalectomy. World Journal of Surgery 32 863872. (https://doi.org/10.1007/s00268-007-9402-y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Brauckhoff M, Machens A, Lorenz K, Bjøro T, Varhaug JE & Dralle H 2014 Surgical curability of medullary thyroid cancer in multiple endocrine neoplasia 2B: a changing perspective. Annals of Surgery 259 800806. (https://doi.org/10.1097/SLA.0b013e3182a6f43a)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Castagna MG, Fugazzola L, Maino F, Covelli D, Memmo S, Sestini F, Fioravanti C, Ferraris Fusarini C, Scapellato C, Macchini F, et al. 2015 Reference range of serum calcitonin in pediatric population. Journal of Clinical Endocrinology and Metabolism 100 17801784. (https://doi.org/10.1210/jc.2014-4508)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Castinetti F, Qi XP, Walz MK, Maia AL, Sansó G, Peczkowska M, Hasse-Lazar K, Links TP, Dvorakova S, Toledo RA, et al. 2014 Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associated with multiple endocrine neoplasia type 2: an international retrospective population-based study. Lancet Oncology 15 648655. (https://doi.org/10.1016/S1470-2045(14)70154-8)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P & Wells SA Jr 1993 Mutations in the RET proto-oncogene are associated with MEN2A and FMTC. Human Molecular Genetics 2 851856. (https://doi.org/10.1093/hmg/2.7.851)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dralle H, Scheumann GF, Kotzerke J & Brabant EG 1992 Surgical management of MEN2. Recent Results in Cancer Research 125 167195.

  • Dralle H, Gimm O, Simon D, Frank-Raue K, Görtz G, Niederle B, Wahl RA, Koch B, Walgenbach S, Hampel R, 1998 Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma: German and Austrian experience. World Journal of Surgery 22 744750. (https://doi.org/10.1007/s002689900463)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Elisei R, Romei C, Renzini G, Bottici V, Cosci B, Molinaro E, Agate L, Cappagli V, Miccoli P, Berti P, 2012 The timing of total thyroidectomy in RET gene mutation carriers could be personalized and safely planned on the basis of serum calcitonin: 18 years experience at one single center. Journal of Clinical Endocrinology and Metabolism 97 426435. (https://doi.org/10.1210/jc.2011-2046)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Eng C, Smith DP, Mulligan LM, Healey CS, Zvelebil MJ, Stonehouse TJ, Ponder MA, Jackson CE, Waterfield MD & Ponder BA 1995 A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. Oncogene 10 509513.

    • Search Google Scholar
    • Export Citation
  • Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Amstel HK, Lips CJ, Nishisho I, Takai SI, et al. 1996 The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. Journal of the American Medical Association 276 15751579. (https://doi.org/10.1001/jama.1996.03540190047028)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Frank-Raue K, Rondot S & Raue F 2010 Molecular genetics and phenomics of RET mutations: impact on prognosis of MTC. Molecular and Cellular Endocrinology 322 27. (https://doi.org/10.1016/j.mce.2010.01.012)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Frank-Raue K, Rybicki LA, Erlic Z, Schweizer H, Winter A, Milos I, Toledo SP, Toledo RA, Tavares MR, Alevizaki M, 2011 International RET Exon 10 Consortium. Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. Human Mutation 32 5158. (https://doi.org/10.1002/humu.21385)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gagel RF, Tashjian AH, Cummings T, Papathanasopoulos N, Kaplan MM, DeLellis RA, Wolfe HJ & Reichlin S 1988 The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. New England Journal of Medicine 318 478484. (https://doi.org/10.1056/NEJM198802253180804)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Graze K, Spiler IJ, Tashjian AH, Melvin KE, Cervi-Skinner S, Gagel RF, Miller HH, Wolfe HJ, DeLellis RA, Leape L, et al. 1978 Natural history of familial medullary thyroid carcinoma. Effect of a program for early diagnosis. New England Journal of Medicine 299 980985. (https://doi.org/10.1056/NEJM197811022991804)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Grubbs EG & Gagel RF 2015 My, how things have changed in multiple endocrine neoplasia type 2A! Journal of Clinical Endocrinology and Metabolism 100 25322535. (https://doi.org/10.1210/jc.2015-2516)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Hofstra RM, Fattoruso O, Quadro L, Wu Y, Libroia A, Verga U, Colantuoni V & Buys CH 1997 A novel point mutation in the intracellular domain of the ret protooncogene in a family with medullary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 82 41764178. (https://doi.org/10.1210/jcem.82.12.4439)

    • Search Google Scholar
    • Export Citation
  • Kluijfhout WP, van Beek DJ, Verrijn Stuart AA, Lodewijk L, Valk GD, van der Zee DC, Vriens MR & Borel Rinkes IH 2015 Postoperative complications after prophylactic thyroidectomy for very young patients with multiple endocrine neoplasia type 2: retrospective cohort analysis. Medicine 94 e1108. (https://doi.org/10.1097/MD.0000000000001108)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lairmore TC, Ball DW, Baylin SB & Wells SA Jr 1993 Management of pheochromocytomas in patients with multiple endocrine neoplasia type 2 syndromes. Annals of Surgery 217 595601. (https://doi.org/10.1097/00000658-199306000-00001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Learoyd DL, Marsh DJ, Richardson AL, Twigg SM, Delbridge L & Robinson BG 1997 Genetic testing for familial cancer. Consequences of RET proto-oncogene mutation analysis in multiple endocrine neoplasia, type 2. Archives of Surgery 132 10221025. (https://doi.org/10.1001/archsurg.1997.01430330088015)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lips CJ, Minder WH, Leo JR, Alleman A & Hackeng WH 1978 Evidence of multicentric origin of the multiple endocrine neoplasia syndrome type 2a (Sipple's syndrome) in a large family in the Netherlands. Diagnostic and therapeutic implications. American Journal of Medicine 64 569578. (https://doi.org/10.1016/0002-9343(78)90575-2)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lips KJ, Van der Sluys Veer J, Struyvenberg A, Alleman A, Leo JR, Wittebol P, Minder WH, Kooiker CJ, Geerdink RA, Van Waes PF, et al. 1981 Bilateral occurrence of pheochromocytoma in patients with the multiple endocrine neoplasia syndrome type 2A (Sipple’s syndrome). American Journal of Medicine 70 10511060. (https://doi.org/10.1016/0002-9343(81)90866-4)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lips CJ, Landsvater RM, Höppener JW, Geerdink RA, Blijham G, van Veen JM, van Gils AP, de Wit MJ, Zewald RA, Berends MJ, et al. 1994 Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. New England Journal of Medicine 331 828835. (https://doi.org/10.1056/NEJM199409293311302)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lora MS, Waguespack SG, Moley JF & Walvoord EC 2005 Adrenal ganglioneuromas in children with multiple endocrine neoplasia type 2: a report of two cases. Journal of Clinical Endocrinology and Metabolism 90 43834387. (https://doi.org/10.1210/jc.2004-2526)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Machens A, Gimm O, Ukkat J, Hinze R, Schneyer U & Dralle H 2000 Improved prediction of calcitonin normalization in medullary thyroid carcinoma patients by quantitative lymph node analysis. Cancer 88 19091915. (https://doi.org/10.1002/(SICI)1097-0142(20000415)88:8<1909::AID-CNCR21>3.0.CO;2-A)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Machens A, Niccoli-Sire P, Hoegel J, Frank-Raue K, van Vroonhoven TJ, Roeher HD, Wahl RA, Lamesch P, Raue F, Conte-Devolx B, et al. 2003 Early malignant progression of hereditary medullary thyroid cancer. New England Journal of Medicine 349 15171525. (https://doi.org/10.1056/NEJMoa012915)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Machens A, Hauptmann S & Dralle H 2009 a Modification of multiple endocrine neoplasia 2A phenotype by cell membrane proximity of RET mutations in exon 10. Endocrine Related Cancer 16 171177. (https://doi.org/10.1677/ERC-08-0096)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Machens A, Lorenz K & Dralle H 2009 b Constitutive RET tyrosine kinase activation in hereditary medullary thyroid cancer: clinical opportunities. Journal of Internal Medicine 266 114125. (https://doi.org/10.1111/j.1365-2796.2009.02113.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Machens A, Lorenz K & Dralle H 2009 c Individualization of lymph node dissection in RET (rearranged during transfection) carriers at risk for medullary thyroid cancer: value of pretherapeutic calcitonin levels. Annals of Surgery 250 305310. (https://doi.org/10.1097/SLA.0b013e3181ae333f)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Machens A, Lorenz K & Dralle H 2013 a Peak incidence of pheochromocytoma and primary hyperparathyroidism in multiple endocrine neoplasia 2: need for age-adjusted biochemical screening. Journal of Clinical Endocrinology and Metabolism 98 E336E345. (https://doi.org/10.1210/jc.2012-3192)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Machens A, Lorenz K, Sekulla C, Höppner W, Frank-Raue K, Raue F & Dralle H 2013 b Molecular epidemiology of multiple endocrine neoplasia 2: implications for RET screening in the new millenium. European Journal of Endocrinology 168 307314. (https://doi.org/10.1530/EJE-12-0919)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Machens A & Dralle H 2015 Therapeutic effectiveness of screening for multiple endocrine neoplasia type 2A. Journal of Clinical Endocrinology and Metabolism 100 25392545. (https://doi.org/10.1210/jc.2015-1689)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Machens A, Elwerr M, Thanh PN, Lorenz K, Schneider R & Dralle H 2016 Impact of central node dissection on postoperative morbidity in pediatric patients with suspected or proven thyroid cancer. Surgery 160 484492. (https://doi.org/10.1016/j.surg.2016.03.007)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Moley JF, Skinner M, Gillanders WE, Lairmore TC, Rowland KJ, Traugott AL, Jin LX & Wells SA Jr 2015 Management of the parathyroid glands during preventive thyroidectomy in patients with multiple endocrine neoplasia type 2. Annals of Surgery 262 641646. (https://doi.org/10.1097/SLA.0000000000001464)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Morris LF, Waguespack SG, Edeiken-Monroe BS, Lee JE, Rich TA, Ying AK, Warneke CL, Evans DB, Perrier ND & Grubbs EG 2013 Ultrasonography should not guide the timing of thyroidectomy in pediatric patients diagnosed with multiple endocrine neoplasia syndrome 2A through genetic screening. Annals of Surgical Oncology 20 5359. (https://doi.org/10.1245/s10434-012-2589-7)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, et al. 1993 Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363 458460. (https://doi.org/10.1038/363458a0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ponder BA, Ponder MA, Coffey R, Pembrey ME, Gagel RF, Telenius-Berg M, Semple P & Easton DF 1988 Risk estimation and screening in families of patients with medullary thyroid carcinoma. Lancet 331 397401. (https://doi.org/10.1016/S0140-6736(88)91191-9)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Rich TA, Feng L, Busaidy N, Cote GJ, Gagel RF, Hu M, Jimenez C, Lee JE, Perrier N, Sherman SI, et al. 2014 Prevalence by age and predictors of medullary thyroid cancer in patients with lower risk germline RET proto-oncogene mutations. Thyroid 24 10961106. (https://doi.org/10.1089/thy.2013.0620)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rodriguez JM, Balsalobre M, Ponce JL, Ríos A, Torregrosa NM, Tebar J & Parrilla P 2008 Pheochromocytoma in MEN2A syndrome. Study of 54 patients. World Journal of Surgery 32 25202526. (https://doi.org/10.1007/s00268-008-9734-2)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rohmer V, Vidal-Trecan G, Bourdelot A, Niccoli P, Murat A, Wemeau JL, Borson-Chazot F, Schvartz C, Tabarin A, Chabre O, 2011 Prognostic factors of disease-free survival after thyroidectomy in 170 young patients with a RET germline mutation: a multicenter study of the Groupe Francais d’Etude des Tumeurs Endocrines. Journal of Clinical Endocrinology and Metabolism 96 E509E518. (https://doi.org/10.1210/jc.2010-1234)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Rowland KJ, Chernock RD & Moley JF 2013 Pheochromocytoma in an 8-year-old patient with multiple endocrine neoplasia type 2A: implications for screening. Journal of Surgical Oncology 108 203206. (https://doi.org/10.1002/jso.23378)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Scollo C, Baudin E, Travagli JP, Caillou B, Bellon N, Leboulleux S & Schlumberger M 2003 Rationale for central and bilateral lymph node dissection in sporadic and hereditary medullary thyroid cancer. Journal of Clinical Endocrinology and Metabolism 88 20702075. (https://doi.org/10.1210/jc.2002-021713)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Scholten A, Valk GD, Ulfman D, Borel Rinkes IH & Vriens MR 2011 Unilateral subtotal adrenalectomy for pheochromocytoma in multiple endocrine neoplasia type 2 patients: a feasible surgical strategy. Annals of Surgery 254 10221027. (https://doi.org/10.1097/SLA.0b013e318237480c)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Schuffenecker I, Ginet N, Goldgar D, Eng C, Chambe B, Boneu A, Houdent C, Pallo D, Schlumberger M, Thivolet C, 1997 Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. Le Groupe d’Etude des Tumeurs à Calcitonine. American Journal of Human Genetics 60 233237. (https://doi.org/10.1210/jcem.83.2.4529)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Schuffenecker I, Virally-Monod M, Brohet R, Goldgar D, Conte-Devolx B, Leclerc L, Chabre O, Boneu A, Caron J, Houdent C, 1998 Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Groupe d'Etude des Tumeurs à Calcitonine. Journal of Clinical Endocrinology and Metabolism 83 487491.

    • Search Google Scholar
    • Export Citation
  • Sipple JH 1961 The association of pheochromocytoma with carcinoma of the thyroid gland. American Journal of Medicine 31 163166. (https://doi.org/10.1016/0002-9343(61)90234-0)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Skinner MA, Moley JA, Dilley WG, Owzar K, DeBenedetti MK & Wells SA Jr 2005 Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. New England Journal of Medicine 353 11051113. (https://doi.org/10.1056/NEJMoa043999)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Wells SA Jr, Chi DD, Toshima K, Dehner LP, Coffin CM, Dowton SB, Ivanovich JL, DeBenedetti MK, Dilley WG, Moley JF, 1994 Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Annals of Surgery 220 237247. (https://doi.org/10.1097/00000658-199409000-00002)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wells SA Jr, Pacini F, Robinson BG & Santoro M 2013 Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. Journal of Clinical Endocrinology and Metabolism 98 31493164. (https://doi.org/10.1210/jc.2013-1204)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, Pacini F, et al. 2015 Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25 567610. (https://doi.org/10.1089/thy.2014.0335)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Williams ED 1965 A review of 17 cases of carcinoma of the thyroid and phaeochromocytoma. Journal of Clinical Pathology 18 288292. (https://doi.org/10.1136/jcp.18.3.288)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yoshida S, Imai T, Kikumori T, Wada M, Sawaki M, Takada H, Yamada T, Sato S, Sassa M, Uchida H, et al. 2009 Long term parathyroid function following total parathyroidectomy with autotransplantation in adult patients with MEN2A. Endocrine Journal 56 545551. (https://doi.org/10.1507/endocrj.K09E-005)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation