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

in Endocrine-Related Cancer
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  • 1 Department of Endocrine Surgery, Aix Marseille University, Assistance Publique Hopitaux de Marseille, La Conception Hospital, Marseille, France
  • 2 Department of Molecular Biology, Aix Marseille University, CNRS UMR 7286, Assistance Publique Hopitaux de Marseille, La Conception Hospital, Marseille, France
  • 3 Department of Nuclear Medicine, Aix Marseille University, Assistance Publique Hopitaux de Marseille, La Timone Hospital, Marseille, France
  • 4 Department of Endocrinology, Aix Marseille University, CNRS UMR7286, Assistance Publique Hopitaux de Marseille, La Conception Hospital, Marseille, France
  • 5 Endocrine Division, Department of Medicine, Centre hospitalier de l’Université de Montréal, Montreal, Quebec, Canada

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

Abstract

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

Introduction

The majority of the studies published on MEN2 focused on medullary thyroid cancer (MTC), as it represents the first manifestation of the disease and can lead to a fatal outcome if undiagnosed or inappropriately treated (Wells et al. 2013). However, in familial cases with early genetic diagnosis, the guidelines recommend prophylactic thyroidectomy leading to the absence of residual thyroid disease (Wells et al. 2015). Thus, the chronic disease risk of MEN2 is the development of pheochromocytoma (PHEO), and less frequently of hyperparathyroidism (HPTH). The aim of this review is first to detail the main characteristics and the management of MEN2 PHEO and then to define the main other etiologies of hereditary bilateral PHEO (Table 1). A similar review will be made for HPTH.

Table 1

Main characteristics of cluster 2 hereditary pheochromocytomas.

DiseaseMultiple endocrine neoplasia type 2Neurofibromatosis type 1Familial PPGL withTMEM127 gene mutationFamilial PPGL withMAX gene mutation
GeneRETNF1TMEM127MAX
Chromosomal locus10q11.2117q11.22q11.214q23.3
Gene functionproto-oncogenetumor suppressor genetumor suppressor genetumor suppressor gene
Genetic Mechanismactivating mutationinactivating mutationinactivating mutationinactivating mutation
InheritanceADADADAD
PhenotypeMultiple Endocrine Neoplasia type 2A MTC (100%), PHEO (50%), primary HPTH (25%), notalgiaMultiple Endocrine Neoplasia type 2B MTC (100%), PHEO (50%), marfanoid habitus, mucosal neuromasNeurofibromas (95%), café au lait spots (90%), iris hamartomas (90%), bony lesion, skinfold freckling (80%), optic pathway tumor (15%). PHEO (0, 1–10%)Single or bilateral PHEO (30–50%); PGL (0–4%), renal cell carcinoma, C cell hyperplasiaBilateral PHEO, thoraco-abdominal PGL, renal oncocytoma
Secretion profileBoth metanephrins and normetanephrinsBoth metanephrins and normetanephrinsMainly metanephrins secretionMainly normetanephrins secretion
PHEO malignancyRare<10%Rare<25%

AD, autosomal dominant; HPTH, hyperparathyroidism; MTC, medullary thyroid carcinoma; PHEO, pheochromocytoma; PGL, paraganglioma; PPGL, pheochromocytoma and paraganglioma.

Pheochromocytoma in MEN2 and non-MEN2 familial forms

PHEO are neuroendocrine tumors arising from adrenal medulla cells. Paragangliomas (PGL) originate form sympathetic or parasympathetic paraganglia; they have rarely been reported in MEN2 patients (less than 1% in our series of 1210 patients with MEN2) (Castinetti et al. 2014), but constitute a unique entity together with PHEO in other hereditary forms. Management of pheochromocytoma requires highly-specialized teams: pre-operative management should be aimed at normalizing blood pressure and heart rate, based on alpha-adrenergic receptor blockers, high sodium diet and fluid intake, 7–14 days before surgery, with a careful monitoring of blood pressure, as stated by the Endocrine Society guidelines (Lenders et al. 2014).

MEN2 PHEO

Epidemiology and genetics

PHEO is the second most frequent disease in patients with MEN2. It is usually diagnosed in the 3rd–4th decade (Nguyen et al. 2001). Even if some reports mentioned the possibility of PHEO first, with a delayed appearance of MTC, PHEO is diagnosed concomitantly or after the diagnosis of MTC in the very large majority of cases. Imai and coworkers reported that 17% of their 144 MEN2 patients were actually diagnosed with PHEO before MTC (Imai et al. 2013), however, calcitonin measurement was not systematically performed, nor, obviously thyroidectomy, and it is thus not sure that these patients indeed had normal C-cells at the time of PHEO diagnosis.

The penetrance and age at diagnosis of PHEO in MEN2 seems to be dependent on the RET mutation. For instance, Imai and coworkers reported that the penetrance of PHEO was 52% by age 50 years in codon 634 RET mutation carriers, while it was 36% at last follow-up in patients with mutations other than codons 634 and 918 (Imai et al. 2013). In our large series based on 563 individuals presenting with MEN2 PHEO, while 60% patients with 634-RET mutations had at least one PHEO at last follow-up (median age at first diagnosis, 35 years), less than 20% of patients carrying with RET exon 10 mutations presented with PHEO at age 35 years (Castinetti et al. 2014). A strong genotype/phenotype correlation thus exists for PHEO penetrance in MEN2 patients. However, we recently reported that the penetrance of PHEO in MEN2 was variable depending on the geographic area, with an age at first diagnosis of PHEO significantly higher in South America than that in Europe (Castinetti et al. 2017). The American Thyroid Association (ATA) guidelines recommended screening for PHEO beginning at 11 years for children in the ATA-high and highest risk (RET codons 634, 883 and 918) and 16 years in the ATA-moderate risk (all the other codons) (Wells et al. 2015). Of note, one case report described the occurrence of PHEO in an 8-year-old boy carrying a 634 RET codon mutation (Rowland et al. 2013).

Interestingly, in MEN2, patients within the same family, i.e. carrying the same mutation and theoretically exposed to the same environment, can present a different penetrance of PHEO (absence, unilateral or bilateral): this might be due to modifying genes as recently suggested to explain at least partly the difference of MTC aggressiveness in patients with MEN2A compared to MEN2B (Oczko-Wojciechowska et al. 2017). Siqueira and coworkers had already shown that RET polymorphisms had an influence on the prevalence of MEN2 PHEO (Siqueira et al. 2014). For instance, the presence of two RET variants among L769L, S836S and G691S/S904S was associated with an increased risk for early PHEO development (Siqueira et al. 2014).

The outcome of MEN2 PHEO is usually good in specialized MEN/endocrine referral centers. Thosani and coworkers reported only 2 deaths out of 84 patients, because of PHEO with hypertensive crises and autopsy diagnosis; however, the diagnostic procedure had been performed in the 1960s, and such events now appear to be very rare in the modern era of PHEO management (Thosani et al. 2013). In our series, 5 deaths (<1%) were due to PHEO, 4 because of hypertensive crises in undiagnosed patients and 1 because of diffuse PHEO metastases (Castinetti et al. 2014).

Diagnosis

Diagnosis follows the same procedure as sporadic PHEO. Of note, in our series, one-third of the patients were not symptomatic (hypertension, headaches, sweating) at the time PHEO was diagnosed (Castinetti et al. 2014). Systematic screening should thus be performed regularly even in the absence of clinical signs suggestive of PHEO. From a pathophysiological viewpoint, adrenomedullary hyperplasia precedes PHEO, and PHEO is frequently multifocal in the same adrenal gland (Korpershoek et al. 2014). Symptoms of catecholamine oversecretion can be already seen at the stage of hyperplasia. The development of PHEO in MEN2 is usually progressive, and bilateral PHEO are not always synchronous: metachronous PHEO have been reported in up to 25% cases after a mean period of 5–10 years (Thosani et al. 2013, Castinetti et al. 2014), requiring a prolonged follow-up after the first surgery. Positive diagnosis is based on increased plasma or urinary fractionated metanephrine and normetanephrine (Bravo & Tagle 2003, Eisenhofer et al. 2011). Imaging should be performed only when biochemistry becomes positive.

Imaging

Once the biochemical diagnosis is established, the PHEO needs to be localized. The commonest approach for localizing PHEO is to perform anatomical imaging studies. Although CT is a radiation-ionizing diagnostic imaging, it provides a higher resolution than MRI enabling detection of unique and multiple PHEO including those that can coexist within the same glands. Most importantly, anatomical imaging may also guides surgeons toward the most appropriate surgical strategy (total vs subtotal). Therefore, the follow-up of MEN2-related PHEO should not be delayed beyond the scheduled time for subtotal adrenalectomy (cortical-sparing surgery). Many of the MEN2 patients do not need any specific functional imaging since the tumors are almost always confined to the adrenal gland and the likelihood of metastasis is very small. Currently, several specific radiopharmaceuticals (123I-MIBG, 18F-FDA, 18F-FDOPA PET and 68Ga-DOTA-somatostatin analogs) are available. The main advantage of 18F-FDOPA compared to other radiopharmaceuticals is the absence or faintly uptake by normal adrenal glands. On 18F-FDOPA PET/CT, uptake should be considered as pathological only in cases of adrenal uptake more intense than the liver with concordant enlarged gland. 18F-FDOPA PET/CT can also detect residual MTC in patients with persistant hypercalcitoninemia (Timmers et al. 2009, Havekes et al. 2010, Taieb et al. 2012, Castinetti et al. 2015, Shamim et al. 2015).

Treatment

Adrenal surgery is the only available treatment: it should be done before thyroid surgery in case of concomitant diagnosis of MTC and PHEO. Adrenalectomy should be performed in PHEO as soon as the biology becomes positive and/or in patients regularly followed for a size cutoff >1 cm. Bilateral adrenalectomy should only be performed when synchronous bilateral PHEO are diagnosed (Lairmore et al. 1993). Interestingly, despite the screening procedures usually leading to smaller PHEO at the time of surgery (compared with sporadic PHEO), the risk of hypertensive episodes during resection is identical: a similar pharmacological preparation predominantly with alpha blockers should thus be performed before surgery (Scholten et al. 2011b).

The question remains on the role of adrenal sparing surgery when bilateral adrenalectomy is required in such patients. We and others have reported the excellent short-term outcomes of such an approach: the idea of adrenal-sparing surgery is to take off the PHEO while maintaining 1/3rd–1/4th of the gland to allow maintenance of a normal cortisol and aldosterone function. Out of 552 patients operated, adrenal sparing surgery was performed in 114 (20.6%). Normal cortisol function was reported in 57% of patients operated for bilateral PHEO with at least 1 sparing surgery (Castinetti et al. 2014). The results were quite the same as those for Grubbs and coworkers with 58% of normal glucocorticoid function in 33 patients operated with adrenal sparing surgery (Grubbs et al. 2013). The main risk of adrenal sparing surgery is PHEO recurrence: indeed, complete adrenal medulla resection is technically impossible, and the risk of recurrence in this germinal disease is thus very high: while we had 3% risk of recurrence after 10 years of follow-up, other series reported 1–11% risk of recurrence after a mean follow-up of 6–10 years after surgery (reviewed in Castinetti et al. 2016). It is likely that this risk will increase dramatically the longer the duration of follow-up. Prolonged follow-up is thus required in these patients. As there is only a very low 1–4% risk of malignancy for MEN2 PHEO (Lee et al. 1996), we suggest that this procedure should be systematically considered in all patients with MEN2 PHEO. Of note, adrenal sparing surgery has an inherent limit due to the pathophysiology of MEN2 as PHEO are frequently multifocal in the same gland, which can make sparing surgery impossible, because of the impossibility to maintain a sufficient amount of normal cortical tissue (Korpershoek et al. 2014). Recurrence after adrenal sparing surgery will be mainly treated by total adrenalectomy, or in some very experienced centers, by another partial adrenalectomy (Brauckhoff et al. 2004).

In summary, PHEO will become the most prevalent disease of MEN2 given the fact that young familial cases are treated by prophylactic thyroidectomy. The majority of the patients will be asymptomatic at the time of diagnosis, which implies a regular biological follow-up in asymptomatic carriers. Being able to perform an early diagnosis of PHEO is mandatory to allow the surgeon to get the possibility to perform adrenal-sparing surgery, and avoid the risk of permanent post-surgical adrenal insufficiency in patients with bilateral PHEO.

Non-MEN2 familial forms: the cluster 2 genes

Transcriptomic studies performed over recent years established a clustered classification for PHEO/PGL (reviewed in Gimenez-Roqueplo et al. 2012, Vicha et al. 2013). Cluster 1 is characterized by activation of the hypoxia-angiogenesis pathway despite normoxia: It includes SDH- and VHL-related tumors. The hypoxia-inducible factor (HIF) is abnormally stabilized due to an impairment in the VHL-mediated degradation system and induces angiogenesis, promoting the development of PHEO and PGL (Eisenhofer et al. 2004, Barontini & Dahia 2010, Jochmanova et al. 2013, 2014). Cluster 2 includes genes which mutations lead to dysregulation of intracellular signaling pathways (PI3K/AKT, MAPK/ERK kinase), triggering tumorigenesis: RET and NF1 activate PI3K/AKT/mTOR and RAS/RAF/MAPK signaling pathways; TMEM127 enhances mTOR activity; MAX modifies the MYC-MAX-MXD1 network connected with mTOR pathway. Recently, based on mRNA analysis, Fishbein and coworkers subdivided the whole group of PHEO/PGL in 4 different entities: Wnt-altered pathway, kinase signaling pathway, pseudohypoxia pathway and what they called cortical admixture (Fishbein et al. 2017). Interestingly, germline mutations in MAX occurred in this specific subgroup and not in the Cluster 2 class (Fishbein et al. 2017). The main pathways involved in PHEO pathogenesis are depicted in Fig. 1 (data from Dahia 2014).

Figure 1
Figure 1

Simplified overview of main genes and pathways involved in PHEO/PGL. Blue boxes, tumor suppressor genes involved in hereditary PHEO/PGL; red boxes, proto-oncogenes involved in hereditary PHEO/PGL; black arrows, simplified Krebs cycle; orange arrows, inhibition effect; dotted arrows, not well-established mechanism; green arrows, stimulating effect. AKT, RAC-alpha serine/threonine-protein kinase; ERK/MAPK1, mitogen-activated protein kinase 1; FH, fumarate hydratase; HIF1α, hypoxia-inducible factor 1 alpha subunit; HIF1β, hypoxia-inducible factor 1 beta subunit; HIF2α/EPAS1, endothelial PAS domain protein 1; IDH, isocitrate dehydrogenase; MAPK pathway, mitogen-activated protein kinase pathway; MAX, MYC-associated factor X; MDH2, malate dehydrogenase 2; mTOR, mammalian target of rapamycin; MYC, MYC proto-oncogene; NF1, neurofibromin 1; PHD/EGLN 1, 2, 3, prolyl hydroxylase domain protein/egl-9 family hypoxia-inducible factor 1, 2, 3; PI3K, phosphatidyIinositol-4,5-bisphosphate 3-kinase; RAS, rat aarcoma oncogene; RET, rearranged during transfection proto-oncogene; SDH, succinate dehydrogenase complex; TMEM127, transmembrane protein 127; VHL, Von Hippel-Lindau tumor suppressor. Data from Dahlia (2014).

Citation: Endocrine-Related Cancer 25, 2; 10.1530/ERC-17-0266

For this review, we will thus specifically focus on the genes classified in the cluster 2, but we will also include MAX. Cluster 1 genes will not be discussed. Of note, the differential diagnosis with MEN2 for cluster 2 is mainly theoretical as normal calcitonin level at the time of PHEO diagnosis will rule out the possibility of MEN2.

NF1

Neurofibromatosis type 1 (NF1 or Von Reklinghausen disease) is an autosomal dominant disease due to mutations of NF1, a tumor suppressor gene. NF1 is mainly characterized by neurofibromas, café au lait spots, optic pathway tumors, iris hamartomas, bony lesions and skinfold freckling (reviewed in Gutmann et al. 2017). PHEO occurs in only 0.1–10% of cases; it is however one the most frequent etiology of hypertension in patients with NF1 (20–50% cases). This low prevalence explains why only case reports and small series have been reported in the literature. Two small studies suggested that NF1 PHEO size was usually smaller at the time of diagnosis despite the fact that the diagnosis was made at a later age than sporadic PHEO (Shinall & Solorzano 2014, Moramarco et al. 2017). This likely explains why Kepenikian and coworkers recently showed that the majority of the patients with NF1 PHEO were not symptomatic at the time of diagnosis, emphasizing the need for systematic biological screening in patients with NF1 (Kepenekian et al. 2016). In the larger study ever published, 41 patients (out of 1415 admitted for PHEO, prevalence 2.9%) with NF1 PHEO were reported: the median age at diagnosis was 41 years (range 14–67); the median size of PHEO at the time of diagnosis was 3.4 cm (range 0.8–9.5). Bilateral pheochromocytomas were identified in 17% of the patients, while metastases were reported in 7%. The majority of patients (91%) had both metanephrine and normetanephrine secretion at diagnosis (Gruber et al. 2017).

PHEO screening in NF1 patients should be based on biology every 3 years beginning at age 10–14 years. In contrast, systematic NF1 genetic screening in patients with an apparently sporadic PHEO is not recommended, unless there are clinical signs suggestive of neurofibromatosis (Bausch et al. 2006). Optimal management of NF1 PHEO is based on adrenalectomy (Gruber et al. 2017).

TMEM127

Germline TMEM127 mutations were first identified as an etiology of PHEO seven years ago (Qin et al. 2010). TMEM127 mutations prevalence is estimated to be around 2% (1.7% out of 1676 patients tested with PHEO and PGL) (Abermil et al. 2012, Bausch et al. 2017). TMEM127 is a tumor suppressor, encoding a transmembrane protein localized in several intracellular organelles (Jiang & Dahia 2011). Mutations of TMEM127 lead to a drastic decreased function of the protein with an anarchic distribution into the cytoplasm, and dysregulate mTORC1 signaling complex activation. In patients with TMEM127 mutations, the age at diagnosis of PHEO was highly variable from 20 to more than 65 years old (mean age at diagnosis, 43 years, similar to the one of patients with sporadic PHEO). One third of patients had bilateral tumors while only 1 had metastases at last follow-up. One third of the patients with TMEM127 mutations had a sporadic appearing benign PHEO. Interestingly, a history of PHEO was observed in only a quarter of familial cases, suggesting a low penetrance, even if the late age at first diagnosis of PHEO might have biased these data because of an insufficient follow-up period (Qin et al. 2010, Yao et al. 2010). Neumann and coworkers expanded the phenotype one year later, by describing the occurrence of PGL in 2 patients (1 with multiple head and neck PGL, 1 with retroperitoneal extra-adrenal tumor), leading to a prevalence of PGL of 4% in this series of 48 patients (Neumann et al. 2011). No patient had a malignant disease (Neumann et al. 2011). Finally, the phenotype has been recently completed with multifocal PHEO and (nodular) adrenal hyperplasia (<1 cm) preceding and/or coexisting with PHEO (Toledo et al. 2015). Abermil and coworkers reported a prevalence of 0.9% (n = 6 patients) of TMEM127 mutations in a large cohort of 642 unrelated patients with negative testing for classical genes of PHEO and paraganglioma (Abermil et al. 2012). The overall characteristics were comparable with a variable age at diagnosis, a sporadic presentation in half of the patients, bilaterality in half of the patients, and the lack of paraganglial tumor. In this series as in the previous one, all the 5 patients with data available on secretion were presenting with higher metanephrine and normetanephrine. Finally, age-related penetrance of TMEM127-PHEO was evaluated in 0% at 0–20 years, 3% at 21–30 years, 15% at 31–40 years, 24% at 41–50 years and 32% at 51–65 years (Toledo, JCEM, 2015). Clinical screening of TMEM127 mutation carriers should start at 20 years of age, while genetic screening of at risk individuals should be performed before this age (Toledo et al. 2015). Of note, large TMEM127 gene deletions or duplications have never been reported in any patient (Abermil et al. 2012). Optimal management of TMEM127 PHEO is based on adrenalectomy. Interestingly, the association between pheochromocytoma/paraganglioma and renal tumors has been reported for TMEM127 mutations (Hernandez et al. 2015). Up to now, roughly 150 patients with TMEM127 mutations have been reported in the literature. For a detailed list of TMEM127 variants reported in the literature, please refer to Supplementary Table 1 (Qin et al. 2010, Neumann et al. 2011, Abermil et al. 2012, Takeichi et al. 2012, Elston et al. 2013, Rattenberry et al. 2013, Curras-Freixes et al. 2015, Toledo et al. 2015, Patocs et al. 2016, Bausch et al. 2017).

MYC associated factor X (MAX)

MAX mutations were first identified as a cause of PHEO 6 years ago (Comino-Mendez et al. 2011). MAX, a tumor suppressor gene, is a component of the MYC-MAX-MXD1 network of basic helix-loop-helix leucine zipper transcription factors, regulating cell proliferation, differentiation and apoptosis. It is likely that MAX acts as a negative regulator of the network: germline mutations of MAX disable its repressing activity and lead to MYC dysregulation and cancer predisposition (Cascon & Robledo 2012). Twelve cases were reported by Comindo-Mendez and coworkers: age at diagnosis ranged from 17 to 47 years old; the majority of the patients were presenting with bilateral PHEO at diagnosis, and 3 patients had metastatic PHEO at last follow-up (Comino-Mendez et al. 2011). These characteristics were confirmed by a second prevalence study in a series of 1694 patients with PHEO and no mutation in other susceptibility genes: 16 MAX mutations were identified in 23 index patients (prevalence, 1.1%). The majority of them had bilateral PHEO, and 16% had additional thoraco-abdominal PGL. Two patients were metastatic at last follow-up. The secretion profile was mainly high secretion of normetanephrine with normal or moderately increased metanephrine. Of note, 2 patients presented a renal carcinoma and a renal oncocytoma (Burnichon et al. 2012). This finding was recently confirmed in the first study reporting a large genomic deletion of MAX in 3 siblings presenting with bilateral PHEO (n = 2) and a renal oncocytoma (n = 1). This could suggest that MAX also acts as a suppressor gene for renal oncocytomas (Korpershoek et al. 2016), and change the way to follow such patients (with a systematic screening for renal cancers on a long-term basis?). Up to now, roughly 60 patients with MAX mutations have been reported in the literature. For a detailed list of cases of MAX variants reported in the literature, please refer to Supplementary Table 2 (Comino-Mendez et al. 2011, 2015, Burnichon et al. 2012, Peczkowska et al. 2013, Welander et al. 2014, Bausch et al. 2017, Romanet et al. 2017).

Hyperparathyroidism in MEN2 and non-MEN2 familial forms

Primary HPTH is a rather frequent disease, with an incidence of 1 per 1000, including 5–10% of hereditary etiology. These genetic etiologies include isolated primary hyperparathyroidism (such as in familial hypocalciuric hypercalcemia) and syndromic HPTH, among which RET mutations. Familial isolated HPTH (FIHP; OMIM 145000) is defined as autosomal dominant hereditary HPTH without any other associated endocrinopathies. In the majority of families, the genetics background remains unknown, but FIHP has been reported to be associated with mutations in the MEN1, CaSR, CDC73 and more recently GCM2 genes (Table 2) (based on (Miedlich et al. 2003, Thakker et al. 2012, Iacobone et al. 2015, Guan et al. 2016,Vargas-Poussou et al. 2016).

Table 2

Etiologies of hereditary HPTH and phenotypic descriptions.

Syndromic hereditary HPTH
DiseaseMultiple endocrine neoplasia type 1HPTH – jaw tumor syndromeMultiple endocrine neoplasia type 4
GeneMEN1CDC73CDKN1B
Gene functiontumor suppressor genetumor suppressor genetumor suppressor gene
Chromoso- mal locus11q13.11q31.212p13.1
InheritageADADAD
PhenotypePrimary HPTH (90%), Neuroendocrine duodenopancreatic tumor (30–70%), pituitary adenoma (30–40%), adrenal tumour (40%)Primary HPTH (95%), parathyroid carcinoma (21%), fibro-osseous tumour (30%), renal tumor (13%), uterine tumour (57% of females) Primary HPTH (81%), pituitary adenoma (46%), gastric and bronchic carcinoid tumours, gastropancreatic tumour, adrenal tumour
Prevalence1/30,000UnknownUnknown
Median age of HPTH20–25 years27 yearsUnknown
DiseaseFamilial Isolated Primary HPTH (FIPH)
GeneGCM2MEN1CaSRCDC73
Gene functionproto-oncogenetumor suppressor geneCaSR signaling pathwaytumor suppressor geneno identified gene
Chromoso- mal locus6p24.211q13.13q21.1 1q31.2
InheritageADADADADAD
PhenotypeIsolated primary HPTHIsolated primary HPTHIsolated primary HPTHIsolated primary HPTHIsolated primary HPTH
PrevalenceUnknown18% of FIPHUnknown7% of FIPH
Median age of HPTHUnknownUnknownUnknownUnknown
DiseaseNeonatal severe HPTHDifferential diagnosis
FHH1FHH2FHH3
GeneCaSRCaSRGNA11AP2S1
Gene functionCaSR signaling pathwayCaSR signaling pathway CaSR signaling pathway CaSR signaling pathway
Chromoso- mal locus3q21.1 3q21.1 19p13.319q13.3
InheritageAR or ADADADAD
PhenotypeServere hypercalcemia, letal without parathyroi- dectomyLonglife hypercalemia, relative hypo- calciuremia, normal or mild elevated PTHLonglife hypercalemia, relative hypo- calciuremia, normal or mild elevated PTHLonglife hypercalemia, relative hypocalciuremia, normal or mild elevated PTH
PrevalenceUnknown1/10,000 to 1/100,000UnknownUnknown
Median age of HPTHNeonatal UnknownUnknownUnknown

AD, autosomal dominant; AR, autosomal recessive; FHH, Familial hypocalciuric hypercalcemia; HPTH, hyperparathyroidism.

MEN2 hyperparathyroidism

Epidemiology and genetics

HPTH penetrance is lower than MTC and PHEO in MEN2. The prevalence is estimated to be 20% in MEN2A cases (while it is always absent in MEN2); some series even reported a much lower prevalence of 5% in patients with RET mutations (Frank-Raue et al. 2011, Elisei et al. 2012, Machens et al. 2013). In MEN2A, hyperparathyroidism seems to be more frequently associated with 634-RET mutations than other codons (Kraimps et al. 1996, Karga et al. 1998, Raue & Frank-Raue 2009, Valdes et al. 2015). Twenty years ago, Schuffenecker and coworkers had reported that the prevalence of hyperparathyroidism did not differ between patients with C634R or other 634 codon mutations; however, there was a wide intervariability among families, with a prevalence varying from 9 to 40% (again suggesting the involvement of modifying or environmental factors) (Schuffenecker et al. 1998).

Parathyroid hyperplasia precedes the development of adenoma formation, but the hyperplasic stage can lead to hypercalcemia (Mete & Asa 2013). Moreover, hyperplasia and adenoma can coexist in several glands at the time of diagnosis, in favor of an asynchronous development of the parathyroid disease in MEN2. This means that at a given time point, some glands can still be normal, and recurrence will happen after a more or less prolonged period of time after partial parathyroidectomy. In contrast, parathyroid carcinoma has never been reported in MEN2. In sporadic hyperparathyroidism, patients are usually older, with a mean age at diagnosis close to 60 years, and they have only 1 pathologic parathyroid gland. In contrast, the mean age at diagnosis of hyperparathyroidism in MEN2 is usually close to 40 years (Kraimps et al. 1996, Schuffenecker et al. 1998, Machens et al. 2013).

MTC precedes hyperparathyroidism, even if some rare cases depicted early diagnosis of hyperparathyroidism (Mian et al. 2009, Magalhaes et al. 2011). MEN2 diagnosis is thus rarely made after an isolated diagnosis of primary hyperparathyroidism. The majority of the patients are asymptomatic at the time of diagnosis (Carling & Udelsman 2005), emphasizing the need for a systematic yearly calcium work-up in patients with MEN2, as stated by the ATA guidelines.

Diagnosis and screening

The ATA recommends to begin screening by age 8 years in patients with MEN2A, and to screen on a yearly basis for biology suggesting hyperparathyroidism in asymptomatic carriers whatever the codon (Wells et al. 2015). The diagnosis procedure is the same as the one performed in sporadic hyperparathyroidism, with at least calcium level and albumin and then PTH, phosphate and urinary calcium (Elisei et al. 2012). In case of positive diagnosis, imaging can be made to help the surgeon, even if multiglandular disease is present in the majority of cases, and bilateral neck compartments exploration is usually mandatory.

Imaging

When HPTH is diagnosed in a MTC patient, minimally invasive parathyroidectomy approach is not a recommended surgical approach for HPTH since bilateral cervicotomy is required for total thyroidectomy. In this situation, neck ultrasound enables preoperative staging of MTC and localization of parathyroid lesions. The role of radionuclide imaging is more limited since ectopic or supernumerary glands are very rare and most of the lesions can be removed via the cervical route. By contrast, when HPTH is diagnosed after thyroidectomy for MTC, preoperative localizing studies are needed for directing focused approaches (concordance between neck ultrasound and PS for the same abnormality). The optimal protocol should use the 99mTc-MIBI/123I subtraction protocol with pinhole acquisition (Hindie et al. 2009, 2015). The use of 4-dimensional computed tomography (4D-CT) for parathyroid imaging has been reported but increases radiation exposure to the patient (Philip et al. 2008). 18F-fluorocholine PET/CT was found to be very sensitive and specific in patients with sporadic primary HPTH or renal HPTH and would need to be evaluated in the setting of MEN2 patients, especially in cases with recurrent HPTH and negative or discordant imaging findings.

Management

In MEN2, management raises the question of the extent of parathyroidectomy, which should be performed when HPTH is diagnosed in the preoperative workup of MTC: total parathyroidectomy, total parathyroidectomy with autotransplantation or selective parathyroidectomy with removal of macroscopically abnormal glands (Herfarth et al. 1996, Yoshida et al. 2009, Scholten et al. 2011a). Total parathyroidectomy without autotransplantation will lead to permanent hypoparathyroidism, a condition not always easy to handle. Recently, Moley and coworkers reported their experience of the management of parathyroid glands during preventive thyroidectomy in patients with MEN2 (Moley et al. 2015). They did not notice any difference between preventive thyroidectomy, central neck dissection, total parathyroidectomy and autotransplantation to the forearm or to the neck, compared to preventive thyroidectomy attempting to preserve the parathyroid glands in situ with an intact vascular pedicle (autotransplantation only if the parathyroid did not seem viable or could not be preserved intact): permanent hypoparathyroidism was not significantly different between both groups (6% vs 1%, P = 0.1) (Moley et al. 2015). Of note, it is not recommended currently to perform systematic parathyroidectomy in patients with MEN2 requiring thyroid surgery for MTC (either prophylactic or not), and still normal PTH and calcium level. In contrast, when HPTH is diagnosed after thyroidectomy, a tailored parathyroidectomy should be performed based, as previously stated, on an exhaustive imaging workup.

Non-MEN2 hyperparathyroidism

Multiple endocrine neoplasia type 1 (MEN1) hyperparathyroidism

One objective of this review is to discuss the novelties of non-MEN2 familial forms of hyperparathyroidism. We thus will not discuss in detail MEN1, but will specifically focus on studies published during the last 3–4 years. Hyperparathyroidism is the earliest and most common feature of MEN1, with a median age at diagnosis of 20–25 years, and a prevalence of almost 100% of cases by age 50–60 years. An epidemiological overview of MEN1 patients diagnosed before age 21 years showed that only 56% of the patients presented with primary hyperparathyroidism as the initial occurring disease in MEN1. The first symptoms appeared before 10 years in 14% of cases, and before 5 in 3% of cases. This emphasizes the need for genetic testing when any of the disease listed as potentially due to MEN1 occurs in a young patient (Goudet et al. 2015). MEN1 genetic screening should be performed in any patient with primary hyperparathyroidism manifestations occurring before age 30 years or in any patient with multiglandular disease whatever the age (Thakker et al. 2012, Lassen et al. 2014).

The natural history of hyperparathyroidism in MEN1 is similar to the one reported for MEN2, with an asynchronous disease (adenoma, hyperplasia on one or several glands) (Mete & Asa 2013). Interestingly, parathyroid carcinoma, though rare, has been reported in patients with MEN1, without certainty that the carcinoma was specific to the menin status. In a series of 348 patients with MEN1 followed in a single tertiary care center (the Mayo Clinic), a prevalence of 0.28% (1 case) of parathyroid carcinoma was reported (Singh Ospina et al. 2014). In parallel, the MD Anderson Cancer Center also identified 2 patients in a series of 291, leading to a prevalence of 0.8%. This may not be different from the prevalence of parathyroid carcinoma in patients with sporadic primary hyperparathyroidism (0.74) (Christakis et al. 2016). The pathological diagnosis of parathyroid carcinoma is usually difficult, and based on invasion of the thyroid, the laryngeal nerve or other neck structures. Treatment is usually based on parathyroidectomy. The main risk is biological recurrence, rather than systemic metastasis, requiring further surgery or the use of cinacalcet (Sensipar), which is marketed in this specific indication (Singh Ospina et al. 2014, Christakis et al. 2016).

Initial surgery mostly relies on subtotal rather than total parathyroidectomy with autotransplantation. In recurrent cases, parathyroid surgery should be repeated after a complete imaging workup to identify the cause (hyperplasia of the parathyroid remnant, supranumerary/ectopic glands) and allow to perform a tailored approach in experienced surgical hands, repeat surgery usually leads to normal calcium levels (when a piece of parathyroid gland is maintained) or to hypoparathyroidism. When surgery is impossible, an alternate medical treatment is possible. Giusti and coworkers recently reported their experience with the use of cinacalcet therapy in patients with MEN1 (Giusti et al. 2016). Cinacalcet is able to bind the calcium sensor receptor and increases its sensitivity to extracellular calcium: this leads to decreased levels of PTH and calcium. In this 12-month multicenter prospective, open-label, non-comparative trial performed in 33 patients with MEN1 (22 with contra-indication or refusal to surgery as a first line treatment, 11 with contra-indications to surgery in a context of recurrent hyperparathyroidism), cinacalcet was able to normalize calcium level in 89% of the patients at the end of the study, with 30 or 60 mg cinacalcet daily. Five patients were excluded because of bad tolerance to the drug, not allowing to adjust the dose of cinacalcet. Of note, no significant change was observed in terms of PTH or urinary calcium at the end of the study (Giusti et al. 2016).

Multiple endocrine neoplasia type 4 (MEN4)

MEN1-like syndrome occurs in 5–10% patients without menin mutations. A subgroup of these patients (roughly 2%) present with CDKN1B (p27) mutations. Identification of p27 mutations were based on a naturally occurring MEN1 rat model (MENX) presenting with an 8 bp homozygous frameshift insertion leading to a premature stop codon in p27 (Pellegata et al. 2006). A small number of patients with heterozygous p27 mutations have been reported since then, characterized by a wide variability in all other diseases classically occurring in MEN1. Primary hyperparathyroidism, in contrast, was present in all published cases, with an identical multiglandular involvement (Agarwal et al. 2009). Interestingly, the V109G p27 variant has been reported as responsible for modifying the natural history of parathyroid involvement in MEN1, based on a cohort of 100 patients paired with 855 controls: V109G variant was associated with a more frequent multiglandular involvement at diagnosis (3–4 vs 1–2 glandular disease) (Longuini et al. 2014).

Hyperparathyroidism-Jaw tumor (HPT-JT) syndrome

HPT-JT is defined by the association of primary hyperparathyroidism, due to a single or multiple parathyroid adenoma or a parathyroid carcinoma (30% cases), and a fibro-osseous jaw tumor (30% cases). Uterine or kidney tumors have also been described as associated with this syndrome. Of note, primary hyperparathyroidism can be isolated at diagnosis, and the penetrance of other diseases is incomplete. Differentiating between MEN1 and HPT-JT can thus be challenging in case of isolated hyperparathyroidism and should lead to genetic testing of both menin and CDC73. HPT-JT is due to mutations of CDC73 (HRPT2) tumor suppressor gene, transmitted as an autosomal dominant trait (Carpten et al. 2002). CDC73 mutations lead to the loss of expression of parafibromin, a nuclear protein involved in chromatin remodeling and histone modification (reviewed in Thakker 2016). Bricaire and coworkers reported the characteristics of 20 index patients with a germinal HRPT2 abnormality: mean age at diagnosis was close to the one reported for MEN1 (23 years), but calcium level at diagnosis was higher (mean, 3.19 mmol/L) (Bricaire et al. 2013). Interestingly, a large deletion of HRPT2 was observed in a third of the cohort patients (Bricaire et al. 2013). Management of HPTH in HPT-JT is based on parathyroidectomy with bilateral neck compartments exploration, given the possible multiglandular and potential malignant nature of the disease. In contrast with sporadic primary hyperparathyroidism, follow-up should be prolonged on a long-term basis to detect recurrence (observed in up to 80% of operated patients) requiring a more aggressive parathyroid surgery (Sarquis et al. 2008). Interestingly, somatic HRPT2 mutations have also been detected in sporadic parathyroid carcinomas, arguing for a role of CDC73 mutations in the overall prognosis of parathyroid disease (Shattuck et al. 2003).

The peculiar case of familial hypocalciuric hypercalcemia

Type 1, 2 and 3 familial hypocalciuric hypercalcemia (FHH) are due to an abnormal inactivation of the calcium sensor receptor signaling pathway. Biological workup usually shows hypercalcemia, unsuppressed PTH level (mostly normal) and not-increased calciuria (low or normal). Basically, any biological phenotype can be seen (Vargas-Poussou et al. 2016). Calcium sensor receptor gene is located in 3q21.1, encoding for the calcium sensor receptor, a transmembrane G protein-coupled receptor. FHH type 1 is due to inactivating mutations of CASr, FHH2 to inactivating GNA11 mutations and FHH3 to mutations of AP2S1, involved in calcium sensor endocytosis. FHH usually leads to parathyroid hyperplasia, even if some operated patients actually presented a true parathyroid adenoma.

Perspectives and conclusions

MEN2 is now a well-characterized disease; while original descriptions were almost exclusively focusing on MTC, reports published over the last 10 years provide more insights into the pathophysiology, diagnosis and management of PHEO, and to a lower extent, HPTH. Both diseases are characterized by a usually benign tumor profile preceded by a hyperplasic stage. Management of such tumors should thus be aimed at curing the disease while preserving an optimal quality of life (partial parathyroidectomy, partial adrenal surgery for instance, should be systematically considered in such patients). Future studies should be aimed at better exploring the phenotypes (with the help of large-scale international networks) and understanding the wide variability presented by the patients in terms of age at diagnosis, asynchronous disease, as this individualized approach will help tailoring the treatment for each patient.

In non-MEN2 familial forms of PHEO and HPTH, the genetic spectrum has drastically changed over the last 10 years, with an increasing rate of new identified genetic etiologies (especially in PHEO). Interestingly, some of these etiologies have also been linked to renal carcinogenesis, and this will be something to take into account when following patients on a long-term basis. New genes are to be identified as recently shown by Fishbein and coworkers: for instance, fusion genes involving MAML3, that have been reported in other tumor types, might play a role in the pathogenesis of hereditary PHEO (Fishbein et al. 2017). In the future, next-generation sequencing approaches will likely lead to focus on different issues, by questioning about the pathogenicity of variants of unknown significance. Moreover, for new genes such as MAX and TMEM127, only little is known about the natural history of PHEO and extra-adrenal features. Large-scale follow-up studies will thus be necessary to adapt the management. New genes are also to be identified as recently shown by Fishbein and coworkers: for instance, fusion genes involving MAML3, that have been reported in other tumor types, might play a role in the pathogenesis of hereditary PHEO (Fishbein, Cancer cell).

Despite the fact that MEN1 has been identified decades ago, and HRPT2 roughly 15 years ago, there is still requirement for further studies, with unresolved questions similar to what we reported for MEN2 (Castinetti et al. 2014): little is known about the factors explaining the wide intra-familial variability of patients carrying with such mutations: the hypotheses of modifying genes/factors or epigenetics should thus pave the way for future research.

Supplementary data

This is linked to the online version of the paper at https://doi.org/10.1530/ERC-17-0266.

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

  • Abermil N, Guillaud-Bataille M, Burnichon N, Venisse A, Manivet P, Guignat L, Drui D, Chupin M, Josseaume C, Affres H, et al. 2012 TMEM127 screening in a large cohort of patients with pheochromocytoma and/or paraganglioma. Journal of Clinical Endocrinology and Metabolism 97 E805E809. (https://doi.org/10.1210/jc.2011-3360)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Agarwal SK, Mateo CM & Marx SJ 2009 Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. Journal of Clinical Endocrinology and Metabolism 94 18261834. (https://doi.org/10.1210/jc.2008-2083)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Barontini M & Dahia PL 2010 VHL disease. Best Practice and Research: Clinical Endocrinology and Metabolism 24 401413. (https://doi.org/10.1016/j.beem.2010.01.002)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bausch B, Koschker AC, Fassnacht M, Stoevesandt J, Hoffmann MM, Eng C, Allolio B & Neumann HP 2006 Comprehensive mutation scanning of NF1 in apparently sporadic cases of pheochromocytoma. Journal of Clinical Endocrinology and Metabolism 91 34783481. (https://doi.org/10.1210/jc.2006-0780)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bausch B, Schiavi F, Ni Y, Welander J, Patocs A, Ngeow J, Wellner U, Malinoc A, Taschin E, Barbon G, et al. 2017 Clinical characterization of the pheochromocytoma and paraganglioma susceptibility genes SDHA, TMEM127, MAX, and SDHAF2 for gene-informed prevention. JAMA Oncology 3 12041212. (https://doi.org/10.1001/jamaoncol.2017.0223)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Brauckhoff M, Gimm O, Brauckhoff K & Dralle H 2004 Repeat adrenocortical-sparing adrenalectomy for recurrent hereditary pheochromocytoma. Surgery Today 34 251255. (https://doi.org/10.1007/s00595-003-2690-4)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bravo EL & Tagle R 2003 Pheochromocytoma: state-of-the-art and future prospects. Endocrine Reviews 24 539553. (https://doi.org/10.1210/er.2002-0013)

  • Bricaire L, Odou MF, Cardot-Bauters C, Delemer B, North MO, Salenave S, Vezzosi D, Kuhn JM, Murat A, Caron P, et al. 2013 Frequent large germline HRPT2 deletions in a French National cohort of patients with primary hyperparathyroidism. Journal of Clinical Endocrinology and Metabolism 98 E403E408. (https://doi.org/10.1210/jc.2012-2789)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Burnichon N, Cascon A, Schiavi F, Morales NP, Comino-Mendez I, Abermil N, Inglada-Perez L, de Cubas AA, Amar L, Barontini M, et al. 2012 MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clinical Cancer Research 18 28282837. (https://doi.org/10.1158/1078-0432.CCR-12-0160)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Carling T & Udelsman R 2005 Parathyroid surgery in familial hyperparathyroid disorders. Journal of Internal Medicine 257 2737. (https://doi.org/10.1111/j.1365-2796.2004.01428.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Carpten JD, Robbins CM, Villablanca A, Forsberg L, Presciuttini S, Bailey-Wilson J, Simonds WF, Gillanders EM, Kennedy AM, Chen JD, et al. 2002 HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nature Genetics 32 676680. (https://doi.org/10.1038/ng1048)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cascon A & Robledo M 2012 MAX and MYC: a heritable breakup. Cancer Research 72 31193124. (https://doi.org/10.1158/0008-5472.CAN-11-3891)

  • Castinetti F, Qi XP, Walz MK, Maia AL, Sanso 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
  • Castinetti F, Kroiss A, Kumar R, Pacak K & Taieb D 2015 15 years of paraganglioma: imaging and imaging-based treatment of pheochromocytoma and paraganglioma. Endocrine-Related Cancer 22 T135T145. (https://doi.org/10.1530/ERC-15-0175)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Castinetti F, Taieb D, Henry JF, Walz M, Guerin C, Brue T, Conte-Devolx B, Neumann HP & Sebag F 2016 Management of endocrine disease: outcome of adrenal sparing surgery in heritable pheochromocytoma. European Journal of Endocrinology 174 R9R18.

    • Search Google Scholar
    • Export Citation
  • Castinetti F, Maia AL, Peczkowska M, Barontini M, Hasse-Lazar K, Links TP, Toledo RA, Dvorakova S, Mian C, Bugalho MJ, et al. 2017 The penetrance of MEN2 pheochromocytoma is not only determined by RET mutations. Endocrine-Related Cancer 24 L63L67. (https://doi.org/10.1530/ERC-17-0189)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Christakis I, Busaidy NL, Cote GJ, Williams MD, Hyde SM, Silva Figueroa AM, Kwatampora LJ, Clarke CN, Qiu W, Lee JE, et al. 2016 Parathyroid carcinoma and atypical parathyroid neoplasms in MEN1 patients; A clinico-pathologic challenge. The MD Anderson case series and review of the literature. International Journal of Surgery 31 1016.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Comino-Mendez I, Gracia-Aznarez FJ, Schiavi F, Landa I, Leandro-Garcia LJ, Leton R, Honrado E, Ramos-Medina R, Caronia D, Pita G, et al. 2011 Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nature Genetics 43 663667. (https://doi.org/10.1038/ng.861)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Comino-Mendez I, Leandro-Garcia LJ, Montoya G, Inglada-Perez L, de Cubas AA, Curras-Freixes M, Tysoe C, Izatt L, Leton R, Gomez-Grana A, et al. 2015 Functional and in silico assessment of MAX variants of unknown significance. Journal of Molecular Medicine 93 12471255. (https://doi.org/10.1007/s00109-015-1306-y)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Curras-Freixes M, Inglada-Perez L, Mancikova V, Montero-Conde C, Leton R, Comino-Mendez I, Apellaniz-Ruiz M, Sanchez-Barroso L, Aguirre Sanchez-Covisa M, Alcazar V, et al. 2015 Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients. Journal of Medical Genetics 52 647656. (https://doi.org/10.1136/jmedgenet-2015-103218)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dahia PL 2014 Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity. Nature Reviews Cancer 14 108119. (https://doi.org/10.1038/nrc3648)

  • Eisenhofer G, Huynh TT, Pacak K, Brouwers FM, Walther MM, Linehan WM, Munson PJ, Mannelli M, Goldstein DS & Elkahloun AG 2004 Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome. Endocrine-Related Cancer 11 897911. (https://doi.org/10.1677/erc.1.00838)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Eisenhofer G, Lenders JW, Timmers H, Mannelli M, Grebe SK, Hofbauer LC, Bornstein SR, Tiebel O, Adams K, Bratslavsky G, et al. 2011 Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. Clinical Chemistry 57 411420. (https://doi.org/10.1373/clinchem.2010.153320)

    • 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, et al. 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
  • Elston MS, Meyer-Rochow GY, Prosser D, Love DR & Conaglen JV 2013 Novel mutation in the TMEM127 gene associated with phaeochromocytoma. Internal Medicine Journal 43 449451. (https://doi.org/10.1111/imj.12088)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fishbein L, Leshchiner I, Walter V, Danilova L, Robertson AG, Johnson AR, Lichtenberg TM, Murray BA, Ghayee HK, Else T, et al. 2017 Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell 31 181193. (https://doi.org/10.1016/j.ccell.2017.01.001)

    • 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, et al. 2011 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
  • Gimenez-Roqueplo AP, Dahia PL & Robledo M 2012 An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes. Hormone and Metabolic Research 44 328333. (https://doi.org/10.1055/s-0031-1301302)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Giusti F, Cianferotti L, Gronchi G, Cioppi F, Masi L, Faggiano A, Colao A, Ferolla P & Brandi ML 2016 Cinacalcet therapy in patients affected by primary hyperparathyroidism associated to Multiple Endocrine Neoplasia Syndrome type 1 (MEN1). Endocrine 52 495506. (https://doi.org/10.1007/s12020-015-0696-5)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Goudet P, Dalac A, Le Bras M, Cardot-Bauters C, Niccoli P, Levy-Bohbot N, du Boullay H, Bertagna X, Ruszniewski P, Borson-Chazot F, et al. 2015 MEN1 disease occurring before 21 years old: a 160-patient cohort study from the Groupe d'etude des Tumeurs Endocrines. Journal of Clinical Endocrinology and Metabolism 100 15681577. (https://doi.org/10.1210/jc.2014-3659)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Grubbs EG, Rich TA, Ng C, Bhosale PR, Jimenez C, Evans DB, Lee JE & Perrier ND 2013 Long-term outcomes of surgical treatment for hereditary pheochromocytoma. Journal of the American College of Surgeons 216 280289. (https://doi.org/10.1016/j.jamcollsurg.2012.10.012)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gruber LM, Erickson D, Babovic-Vuksanovic D, Thompson GB, Young WF Jr & Bancos I 2017 Pheochromocytoma and paraganglioma in patients with neurofibromatosis type 1. Clinical Endocrinology 86 141149. (https://doi.org/10.1111/cen.13163)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Guan B, Welch JM, Sapp JC, Ling H, Li Y, Johnston JJ, Kebebew E, Biesecker LG, Simonds WF, Marx SJ, et al. 2016 GCM2-activating mutations in familial isolated hyperparathyroidism. American Journal of Human Genetics 99 10341044. (https://doi.org/10.1016/j.ajhg.2016.08.018)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gutmann DH, Ferner RE, Listernick RH, Korf BR, Wolters PL & Johnson KJ 2017 Neurofibromatosis type 1. Nature Reviews Disease Primers 3 17004. (https://doi.org/10.1038/nrdp.2017.4)

  • Havekes B, King K, Lai EW, Romijn JA, Corssmit EP & Pacak K 2010 New imaging approaches to phaeochromocytomas and paragangliomas. Clinical Endocrinology 72 137145. (https://doi.org/10.1111/j.1365-2265.2009.03648.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Herfarth KK, Bartsch D, Doherty GM, Wells SA Jr & Lairmore TC 1996 Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Surgery 120 966973. (https://doi.org/10.1016/S0039-6060(96)80042-0)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hernandez KG, Ezzat S, Morel CF, Swallow C, Otremba M, Dickson BC, Asa SL & Mete O 2015 Familial pheochromocytoma and renal cell carcinoma syndrome: TMEM127 as a novel candidate gene for the association. Virchows Archiv 466 727732. (https://doi.org/10.1007/s00428-015-1755-2)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Hindie E, Ugur O, Fuster D, O'Doherty M, Grassetto G, Urena P, Kettle A, Gulec SA, Pons F, Rubello D, et al. 2009 EANM parathyroid guidelines. European Journal of Nuclear Medicine and Molecular Imaging 36 12011216. (https://doi.org/10.1007/s00259-009-1131-z)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hindie E, Zanotti-Fregonara P, Tabarin A, Rubello D, Morelec I, Wagner T, Henry JF & Taieb D 2015 The role of radionuclide imaging in the surgical management of primary hyperparathyroidism. Journal of Nuclear Medicine 56 737744. (https://doi.org/10.2967/jnumed.115.156018)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Iacobone M, Carnaille B, Palazzo FF & Vriens M 2015 Hereditary hyperparathyroidism – a consensus report of the European Society of Endocrine Surgeons (ESES). Langenbeck's Archives of Surgery 400 867886. (https://doi.org/10.1007/s00423-015-1342-7)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Imai T, Uchino S, Okamoto T, Suzuki S, Kosugi S, Kikumori T, Sakurai A & Japan MENCo 2013 High penetrance of pheochromocytoma in multiple endocrine neoplasia 2 caused by germ line RET codon 634 mutation in Japanese patients. European Journal of Endocrinology 168 683687. (https://doi.org/10.1530/EJE-12-1106)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jiang S & Dahia PL 2011 Minireview: the busy road to pheochromocytomas and paragangliomas has a new member, TMEM127. Endocrinology 152 21332140. (https://doi.org/10.1210/en.2011-0052)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Jochmanova I, Yang C, Zhuang Z & Pacak K 2013 Hypoxia-inducible factor signaling in pheochromocytoma: turning the rudder in the right direction. Journal of the National Cancer Institute 105 12701283. (https://doi.org/10.1093/jnci/djt201)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jochmanova I, Zelinka T, Widimsky J Jr & Pacak K 2014 HIF signaling pathway in pheochromocytoma and other neuroendocrine tumors. Physiological Research 63 (Supplement 2) S251S262.

    • Search Google Scholar
    • Export Citation
  • Karga HJ, Karayianni MK, Linos DA, Tseleni SC, Karaiskos KD & Papapetrou PD 1998 Germ line mutation analysis in families with multiple endocrine neoplasia type 2A or familial medullary thyroid carcinoma. European Journal of Endocrinology 139 410415. (https://doi.org/10.1530/eje.0.1390410)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kepenekian L, Mognetti T, Lifante JC, Giraudet AL, Houzard C, Pinson S, Borson-Chazot F & Combemale P 2016 Interest of systematic screening of pheochromocytoma in patients with neurofibromatosis type 1. European Journal of Endocrinology 175 335344. (https://doi.org/10.1530/EJE-16-0233)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Korpershoek E, Petri BJ, Post E, van Eijck CH, Oldenburg RA, Belt EJ, de Herder WW, de Krijger RR & Dinjens WN 2014 Adrenal medullary hyperplasia is a precursor lesion for pheochromocytoma in MEN2 syndrome. Neoplasia 16 868873. (https://doi.org/10.1016/j.neo.2014.09.002)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Korpershoek E, Koffy D, Eussen BH, Oudijk L, Papathomas TG, van Nederveen FH, Belt EJ, Franssen GJ, Restuccia DF, Krol NM, et al. 2016 Complex MAX rearrangement in a family with malignant pheochromocytoma, renal oncocytoma, and erythrocytosis. Journal of Clinical Endocrinology and Metabolism 101 453460. (https://doi.org/10.1210/jc.2015-2592)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kraimps JL, Denizot A, Carnaille B, Henry JF, Proye C, Bacourt F, Sarfati E, Dupond JL, Maes B, Travagli JP, et al. 1996 Primary hyperparathyroidism in multiple endocrine neoplasia type IIa: retrospective French multicentric study. Groupe d'Etude des Tumeurs a Calcitonine (GETC, French Calcitonin Tumors Study Group), French Association of Endocrine Surgeons. World Journal of Surgery 20 808812. (https://doi.org/10.1007/s002689900123)

    • Crossref
    • 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
  • Lassen T, Friis-Hansen L, Rasmussen AK, Knigge U & Feldt-Rasmussen U 2014 Primary hyperparathyroidism in young people. When should we perform genetic testing for multiple endocrine neoplasia 1 (MEN-1)? Journal of Clinical Endocrinology and Metabolism 99 39833987. (https://doi.org/10.1210/jc.2013-4491)

    • Search Google Scholar
    • Export Citation
  • Lee JE, Curley SA, Gagel RF, Evans DB & Hickey RC 1996 Cortical-sparing adrenalectomy for patients with bilateral pheochromocytoma. Surgery 120 10641070. (https://doi.org/10.1016/S0039-6060(96)80056-0)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, Naruse M, Pacak K, Young WF Jr & Endocrine S 2014 Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 99 19151942. (https://doi.org/10.1210/jc.2014-1498)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Longuini VC, Lourenco DM Jr, Sekiya T, Meirelles O, Goncalves TD, Coutinho FL, Francisco G, Osaki LH, Chammas R, Alves VA, et al. 2014 Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations. European Journal of Endocrinology 171 335342. (https://doi.org/10.1530/EJE-14-0130)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Machens A, Lorenz K & Dralle H 2013 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 E336345. (https://doi.org/10.1210/jc.2012-3192)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Magalhaes PK, Antonini SR, de Paula FJ, de Freitas LC & Maciel LM 2011 Primary hyperparathyroidism as the first clinical manifestation of multiple endocrine neoplasia type 2A in a 5-year-old child. Thyroid 21 547550. (https://doi.org/10.1089/thy.2010.0336)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Mete O & Asa SL 2013 Precursor lesions of endocrine system neoplasms. Pathology 45 316330. (https://doi.org/10.1097/PAT.0b013e32835f45c5)

  • Mian C, Barollo S, Zambonin L, Pennelli G, Bernante P, Pelizzo MR, Nacamulli D, Mantero F, Girelli ME & Opocher G 2009 Characterization of the largest kindred with MEN2A due to a Cys609Ser RET mutation. Familial Cancer 8 379382. (https://doi.org/10.1007/s10689-009-9250-z)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Miedlich S, Krohn K & Paschke R 2003 Update on genetic and clinical aspects of primary hyperparathyroidism. Clinical Endocrinology 59 539554. (https://doi.org/10.1046/j.1365-2265.2003.bib1-1-01755.x)

    • 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
  • Moramarco J, El Ghorayeb N, Dumas N, Nolet S, Boulanger L, Burnichon N, Lacroix A, Elhaffaf Z, Gimenez Roqueplo AP, Hamet P, et al. 2017 Pheochromocytomas are diagnosed incidentally and at older age in neurofibromatosis type 1. Clinical Endocrinology 86 332339. (https://doi.org/10.1111/cen.13265)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Neumann HP, Sullivan M, Winter A, Malinoc A, Hoffmann MM, Boedeker CC, Bertz H, Walz MK, Moeller LC, Schmid KW, et al. 2011 Germline mutations of the TMEM127 gene in patients with paraganglioma of head and neck and extraadrenal abdominal sites. Journal of Clinical Endocrinology and Metabolism 96 E1279E1282. (https://doi.org/10.1210/jc.2011-0114)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Nguyen L, Niccoli-Sire P, Caron P, Bastie D, Maes B, Chabrier G, Chabre O, Rohmer V, Lecomte P, Henry JF, et al. 2001 Pheochromocytoma in multiple endocrine neoplasia type 2: a prospective study. European Journal of Endocrinology 144 3744. (https://doi.org/10.1530/eje.0.1440037)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Oczko-Wojciechowska M, Swierniak M, Krajewska J, Kowalska M, Kowal M, Stokowy T, Wojtas B, Rusinek D, Pawlaczek A, Czarniecka A, et al. 2017 Differences in the transcriptome of medullary thyroid cancer regarding the status and type of RET gene mutations. Scientific Reports 7 42074. (https://doi.org/10.1038/srep42074)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Patocs A, Lendvai NK, Butz H, Liko I, Sapi Z, Szucs N, Toth G, Grolmusz VK, Igaz P, Toth M, et al. 2016 Novel SDHB and TMEM127 mutations in patients with pheochromocytoma/paraganglioma syndrome. Pathology and Oncology Research 22 673679. (https://doi.org/10.1007/s12253-016-0050-0)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Peczkowska M, Kowalska A, Sygut J, Waligorski D, Malinoc A, Janaszek-Sitkowska H, Prejbisz A, Januszewicz A & Neumann HP 2013 Testing new susceptibility genes in the cohort of apparently sporadic phaeochromocytoma/paraganglioma patients with clinical characteristics of hereditary syndromes. Clinical Endocrinology 79 817823. (https://doi.org/10.1111/cen.12218)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pellegata NS, Quintanilla-Martinez L, Siggelkow H, Samson E, Bink K, Hofler H, Fend F, Graw J & Atkinson MJ 2006 Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. PNAS 103 1555815563. (https://doi.org/10.1073/pnas.0603877103)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Philip M, Guerrero MA, Evans DB, Hunter GJ, Edeiken-Monroe BS, Vu T & Perrier ND 2008 Efficacy of 4D-CT preoperative localization in 2 patients with MEN 2A. Journal of Surgical Education 65 182185. (https://doi.org/10.1016/j.jsurg.2008.02.003)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Qin Y, Yao L, King EE, Buddavarapu K, Lenci RE, Chocron ES, Lechleiter JD, Sass M, Aronin N, Schiavi F, et al. 2010 Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nature Genetics 42 229233. (https://doi.org/10.1038/ng.533)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rattenberry E, Vialard L, Yeung A, Bair H, McKay K, Jafri M, Canham N, Cole TR, Denes J, Hodgson SV, et al. 2013 A comprehensive next generation sequencing-based genetic testing strategy to improve diagnosis of inherited pheochromocytoma and paraganglioma. Journal of Clinical Endocrinology and Metabolism 98 E1248E1256. (https://doi.org/10.1210/jc.2013-1319)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Raue F & Frank-Raue K 2009 Genotype-phenotype relationship in multiple endocrine neoplasia type 2. Implications for Clinical Management: Hormones 8 2328. (https://doi.org/10.14310/horm.2002.1218)

    • Search Google Scholar
    • Export Citation
  • Romanet P, Guerin C, Pedini P, Essamet W, Castinetti F, Sebag F, Roche P, Cascon A, Tischler AS, Pacak K, et al. 2017 Pathological and genetic characterization of bilateral adrenomedullary hyperplasia in a patient with germline MAX mutation. Endocrine Pathology 28 302307. (https://doi.org/10.1007/s12022-016-9460-5)

    • 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
  • Sarquis MS, Silveira LG, Pimenta FJ, Dias EP, Teh BT, Friedman E, Gomez RS, Tavares GC, Eng C & De Marco L 2008 Familial hyperparathyroidism: surgical outcome after 30 years of follow-up in three families with germline HRPT2 mutations. Surgery 143 630640. (https://doi.org/10.1016/j.surg.2007.12.012)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Scholten A, Schreinemakers JM, Pieterman CR, Valk GD, Vriens MR & Borel Rinkes IH 2011 a Evolution of surgical treatment of primary hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Endocrine Practice 17 715. (https://doi.org/10.4158/EP10050.OR)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Scholten A, Vriens MR, Cromheecke GJ, Borel Rinkes IH & Valk GD 2011 b Hemodynamic instability during resection of pheochromocytoma in MEN versus non-MEN patients. European Journal of Endocrinology 165 9196. (https://doi.org/10.1530/EJE-11-0148)

    • Crossref
    • 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, et al. 1998 Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Journal of Clinical Endocrinology and Metabolism 83 487491.

    • Search Google Scholar
    • Export Citation
  • Shamim SA, Kumar A & Kumar R 2015 PET/computed tomography in neuroendocrine tumor: value to patient management and survival outcomes. PET Clinics 10 411421. (https://doi.org/10.1016/j.cpet.2015.03.005)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Shattuck TM, Valimaki S, Obara T, Gaz RD, Clark OH, Shoback D, Wierman ME, Tojo K, Robbins CM, Carpten JD, et al. 2003 Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. New England Journal of Medicine 349 17221729. (https://doi.org/10.1056/NEJMoa031237)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Shinall MC & Solorzano CC 2014 Pheochromocytoma in neurofibromatosis type 1: when should it be suspected? Endocrine Practice 20 792796. (https://doi.org/10.4158/EP13417.OR)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Singh Ospina N, Sebo TJ, Thompson GB, Clarke BL & Young WF Jr 2014 Prevalence of parathyroid carcinoma in 348 patients with multiple endocrine neoplasia type 1 – case report and review of the literature. Clinical Endocrinology [epub]. (https://doi.org/10.1111/cen.12714)

    • Search Google Scholar
    • Export Citation
  • Siqueira DR, Ceolin L, Ferreira CV, Romitti M, Maia SC, Maciel LM & Maia AL 2014 Role of RET genetic variants in MEN2-associated pheochromocytoma. European Journal of Endocrinology 170 821828. (https://doi.org/10.1530/EJE-14-0084)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Taieb D, Timmers HJ, Hindie E, Guillet BA, Neumann HP, Walz MK, Opocher G, de Herder WW, Boedeker CC, de Krijger RR, et al. 2012 EANM 2012 guidelines for radionuclide imaging of phaeochromocytoma and paraganglioma. European Journal of Nuclear Medicine and Molecular Imaging 39 19771995. (https://doi.org/10.1007/s00259-012-2215-8)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Takeichi N, Midorikawa S, Watanabe A, Naing BT, Tamura H, Wakakuri-Kano T, Ishizaki A, Sugihara H, Nissato S, Saito Y, et al. 2012 Identical germline mutations in the TMEM127 gene in two unrelated Japanese patients with bilateral pheochromocytoma. Clinical Endocrinology 77 707714. (https://doi.org/10.1111/j.1365-2265.2012.04421.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Thakker RV 2016 Genetics of parathyroid tumours. Journal of Internal Medicine 280 574583. (https://doi.org/10.1111/joim.12523)

  • Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F, Brandi ML, et al. 2012 Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). Journal of Clinical Endocrinology and Metabolism 97 29903011. (https://doi.org/10.1210/jc.2012-1230)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Thosani S, Ayala-Ramirez M, Palmer L, Hu MI, Rich T, Gagel RF, Cote G, Waguespack SG, Habra MA & Jimenez C 2013 The characterization of pheochromocytoma and its impact on overall survival in multiple endocrine neoplasia type 2. Journal of Clinical Endocrinology and Metabolism 98 E1813E1819. (https://doi.org/10.1210/jc.2013-1653)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Timmers HJ, Chen CC, Carrasquillo JA, Whatley M, Ling A, Havekes B, Eisenhofer G, Martiniova L, Adams KT & Pacak K 2009 Comparison of 18F-fluoro-L-DOPA, 18F-fluoro-deoxyglucose, and 18F-fluorodopamine PET and 123I-MIBG scintigraphy in the localization of pheochromocytoma and paraganglioma. Journal of Clinical Endocrinology and Metabolism 94 47574767. (https://doi.org/10.1210/jc.2009-1248)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Toledo SP, Lourenco DM Jr., Sekiya T, Lucon AM, Baena ME, Castro CC, Bortolotto LA, Zerbini MC, Siqueira SA, Toledo RA, et al. 2015 Penetrance and clinical features of pheochromocytoma in a six-generation family carrying a germline TMEM127 mutation. Journal of Clinical Endocrinology and Metabolism 100 E308E318. (https://doi.org/10.1210/jc.2014-2473)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Valdes N, Navarro E, Mesa J, Casteras A, Alcazar V, Lamas C, Tebar J, Castano L, Gaztambide S & Forga L 2015 RET Cys634Arg mutation confers a more aggressive multiple endocrine neoplasia type 2A phenotype than Cys634Tyr mutation. European Journal of Endocrinology 172 301307. (https://doi.org/10.1530/EJE-14-0818)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Vargas-Poussou R, Mansour-Hendili L, Baron S, Bertocchio JP, Travers C, Simian C, Treard C, Baudouin V, Beltran S, Broux F, et al. 2016 Familial hypocalciuric hypercalcemia types 1 and 3 and primary hyperparathyroidism: similarities and differences. Journal of Clinical Endocrinology and Metabolism 101 21852195. (https://doi.org/10.1210/jc.2015-3442)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Vicha A, Musil Z & Pacak K 2013 Genetics of pheochromocytoma and paraganglioma syndromes: new advances and future treatment options. Current Opinion in Endocrinology, Diabetes, and Obesity 20 186191. (https://doi.org/10.1097/MED.0b013e32835fcc45)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Welander J, Andreasson A, Juhlin CC, Wiseman RW, Backdahl M, Hoog A, Larsson C, Gimm O & Soderkvist P 2014 Rare germline mutations identified by targeted next-generation sequencing of susceptibility genes in pheochromocytoma and paraganglioma. Journal of Clinical Endocrinology and Metabolism 99 E1352E1360. (https://doi.org/10.1210/jc.2013-4375)

    • Crossref
    • 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
  • Yao L, Schiavi F, Cascon A, Qin Y, Inglada-Perez L, King EE, Toledo RA, Ercolino T, Rapizzi E, Ricketts CJ, et al. 2010 Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas. JAMA 304 26112619. (https://doi.org/10.1210/jc.2013-1204)

    • 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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    Simplified overview of main genes and pathways involved in PHEO/PGL. Blue boxes, tumor suppressor genes involved in hereditary PHEO/PGL; red boxes, proto-oncogenes involved in hereditary PHEO/PGL; black arrows, simplified Krebs cycle; orange arrows, inhibition effect; dotted arrows, not well-established mechanism; green arrows, stimulating effect. AKT, RAC-alpha serine/threonine-protein kinase; ERK/MAPK1, mitogen-activated protein kinase 1; FH, fumarate hydratase; HIF1α, hypoxia-inducible factor 1 alpha subunit; HIF1β, hypoxia-inducible factor 1 beta subunit; HIF2α/EPAS1, endothelial PAS domain protein 1; IDH, isocitrate dehydrogenase; MAPK pathway, mitogen-activated protein kinase pathway; MAX, MYC-associated factor X; MDH2, malate dehydrogenase 2; mTOR, mammalian target of rapamycin; MYC, MYC proto-oncogene; NF1, neurofibromin 1; PHD/EGLN 1, 2, 3, prolyl hydroxylase domain protein/egl-9 family hypoxia-inducible factor 1, 2, 3; PI3K, phosphatidyIinositol-4,5-bisphosphate 3-kinase; RAS, rat aarcoma oncogene; RET, rearranged during transfection proto-oncogene; SDH, succinate dehydrogenase complex; TMEM127, transmembrane protein 127; VHL, Von Hippel-Lindau tumor suppressor. Data from Dahlia (2014).

  • Abermil N, Guillaud-Bataille M, Burnichon N, Venisse A, Manivet P, Guignat L, Drui D, Chupin M, Josseaume C, Affres H, et al. 2012 TMEM127 screening in a large cohort of patients with pheochromocytoma and/or paraganglioma. Journal of Clinical Endocrinology and Metabolism 97 E805E809. (https://doi.org/10.1210/jc.2011-3360)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Agarwal SK, Mateo CM & Marx SJ 2009 Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. Journal of Clinical Endocrinology and Metabolism 94 18261834. (https://doi.org/10.1210/jc.2008-2083)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Barontini M & Dahia PL 2010 VHL disease. Best Practice and Research: Clinical Endocrinology and Metabolism 24 401413. (https://doi.org/10.1016/j.beem.2010.01.002)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bausch B, Koschker AC, Fassnacht M, Stoevesandt J, Hoffmann MM, Eng C, Allolio B & Neumann HP 2006 Comprehensive mutation scanning of NF1 in apparently sporadic cases of pheochromocytoma. Journal of Clinical Endocrinology and Metabolism 91 34783481. (https://doi.org/10.1210/jc.2006-0780)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bausch B, Schiavi F, Ni Y, Welander J, Patocs A, Ngeow J, Wellner U, Malinoc A, Taschin E, Barbon G, et al. 2017 Clinical characterization of the pheochromocytoma and paraganglioma susceptibility genes SDHA, TMEM127, MAX, and SDHAF2 for gene-informed prevention. JAMA Oncology 3 12041212. (https://doi.org/10.1001/jamaoncol.2017.0223)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Brauckhoff M, Gimm O, Brauckhoff K & Dralle H 2004 Repeat adrenocortical-sparing adrenalectomy for recurrent hereditary pheochromocytoma. Surgery Today 34 251255. (https://doi.org/10.1007/s00595-003-2690-4)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bravo EL & Tagle R 2003 Pheochromocytoma: state-of-the-art and future prospects. Endocrine Reviews 24 539553. (https://doi.org/10.1210/er.2002-0013)

  • Bricaire L, Odou MF, Cardot-Bauters C, Delemer B, North MO, Salenave S, Vezzosi D, Kuhn JM, Murat A, Caron P, et al. 2013 Frequent large germline HRPT2 deletions in a French National cohort of patients with primary hyperparathyroidism. Journal of Clinical Endocrinology and Metabolism 98 E403E408. (https://doi.org/10.1210/jc.2012-2789)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Burnichon N, Cascon A, Schiavi F, Morales NP, Comino-Mendez I, Abermil N, Inglada-Perez L, de Cubas AA, Amar L, Barontini M, et al. 2012 MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clinical Cancer Research 18 28282837. (https://doi.org/10.1158/1078-0432.CCR-12-0160)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Carling T & Udelsman R 2005 Parathyroid surgery in familial hyperparathyroid disorders. Journal of Internal Medicine 257 2737. (https://doi.org/10.1111/j.1365-2796.2004.01428.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Carpten JD, Robbins CM, Villablanca A, Forsberg L, Presciuttini S, Bailey-Wilson J, Simonds WF, Gillanders EM, Kennedy AM, Chen JD, et al. 2002 HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nature Genetics 32 676680. (https://doi.org/10.1038/ng1048)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cascon A & Robledo M 2012 MAX and MYC: a heritable breakup. Cancer Research 72 31193124. (https://doi.org/10.1158/0008-5472.CAN-11-3891)

  • Castinetti F, Qi XP, Walz MK, Maia AL, Sanso 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
  • Castinetti F, Kroiss A, Kumar R, Pacak K & Taieb D 2015 15 years of paraganglioma: imaging and imaging-based treatment of pheochromocytoma and paraganglioma. Endocrine-Related Cancer 22 T135T145. (https://doi.org/10.1530/ERC-15-0175)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Castinetti F, Taieb D, Henry JF, Walz M, Guerin C, Brue T, Conte-Devolx B, Neumann HP & Sebag F 2016 Management of endocrine disease: outcome of adrenal sparing surgery in heritable pheochromocytoma. European Journal of Endocrinology 174 R9R18.

    • Search Google Scholar
    • Export Citation
  • Castinetti F, Maia AL, Peczkowska M, Barontini M, Hasse-Lazar K, Links TP, Toledo RA, Dvorakova S, Mian C, Bugalho MJ, et al. 2017 The penetrance of MEN2 pheochromocytoma is not only determined by RET mutations. Endocrine-Related Cancer 24 L63L67. (https://doi.org/10.1530/ERC-17-0189)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Christakis I, Busaidy NL, Cote GJ, Williams MD, Hyde SM, Silva Figueroa AM, Kwatampora LJ, Clarke CN, Qiu W, Lee JE, et al. 2016 Parathyroid carcinoma and atypical parathyroid neoplasms in MEN1 patients; A clinico-pathologic challenge. The MD Anderson case series and review of the literature. International Journal of Surgery 31 1016.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Comino-Mendez I, Gracia-Aznarez FJ, Schiavi F, Landa I, Leandro-Garcia LJ, Leton R, Honrado E, Ramos-Medina R, Caronia D, Pita G, et al. 2011 Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nature Genetics 43 663667. (https://doi.org/10.1038/ng.861)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Comino-Mendez I, Leandro-Garcia LJ, Montoya G, Inglada-Perez L, de Cubas AA, Curras-Freixes M, Tysoe C, Izatt L, Leton R, Gomez-Grana A, et al. 2015 Functional and in silico assessment of MAX variants of unknown significance. Journal of Molecular Medicine 93 12471255. (https://doi.org/10.1007/s00109-015-1306-y)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Curras-Freixes M, Inglada-Perez L, Mancikova V, Montero-Conde C, Leton R, Comino-Mendez I, Apellaniz-Ruiz M, Sanchez-Barroso L, Aguirre Sanchez-Covisa M, Alcazar V, et al. 2015 Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients. Journal of Medical Genetics 52 647656. (https://doi.org/10.1136/jmedgenet-2015-103218)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dahia PL 2014 Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity. Nature Reviews Cancer 14 108119. (https://doi.org/10.1038/nrc3648)

  • Eisenhofer G, Huynh TT, Pacak K, Brouwers FM, Walther MM, Linehan WM, Munson PJ, Mannelli M, Goldstein DS & Elkahloun AG 2004 Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome. Endocrine-Related Cancer 11 897911. (https://doi.org/10.1677/erc.1.00838)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Eisenhofer G, Lenders JW, Timmers H, Mannelli M, Grebe SK, Hofbauer LC, Bornstein SR, Tiebel O, Adams K, Bratslavsky G, et al. 2011 Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. Clinical Chemistry 57 411420. (https://doi.org/10.1373/clinchem.2010.153320)

    • 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, et al. 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
  • Elston MS, Meyer-Rochow GY, Prosser D, Love DR & Conaglen JV 2013 Novel mutation in the TMEM127 gene associated with phaeochromocytoma. Internal Medicine Journal 43 449451. (https://doi.org/10.1111/imj.12088)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fishbein L, Leshchiner I, Walter V, Danilova L, Robertson AG, Johnson AR, Lichtenberg TM, Murray BA, Ghayee HK, Else T, et al. 2017 Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell 31 181193. (https://doi.org/10.1016/j.ccell.2017.01.001)

    • 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, et al. 2011 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
  • Gimenez-Roqueplo AP, Dahia PL & Robledo M 2012 An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes. Hormone and Metabolic Research 44 328333. (https://doi.org/10.1055/s-0031-1301302)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Giusti F, Cianferotti L, Gronchi G, Cioppi F, Masi L, Faggiano A, Colao A, Ferolla P & Brandi ML 2016 Cinacalcet therapy in patients affected by primary hyperparathyroidism associated to Multiple Endocrine Neoplasia Syndrome type 1 (MEN1). Endocrine 52 495506. (https://doi.org/10.1007/s12020-015-0696-5)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Goudet P, Dalac A, Le Bras M, Cardot-Bauters C, Niccoli P, Levy-Bohbot N, du Boullay H, Bertagna X, Ruszniewski P, Borson-Chazot F, et al. 2015 MEN1 disease occurring before 21 years old: a 160-patient cohort study from the Groupe d'etude des Tumeurs Endocrines. Journal of Clinical Endocrinology and Metabolism 100 15681577. (https://doi.org/10.1210/jc.2014-3659)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Grubbs EG, Rich TA, Ng C, Bhosale PR, Jimenez C, Evans DB, Lee JE & Perrier ND 2013 Long-term outcomes of surgical treatment for hereditary pheochromocytoma. Journal of the American College of Surgeons 216 280289. (https://doi.org/10.1016/j.jamcollsurg.2012.10.012)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gruber LM, Erickson D, Babovic-Vuksanovic D, Thompson GB, Young WF Jr & Bancos I 2017 Pheochromocytoma and paraganglioma in patients with neurofibromatosis type 1. Clinical Endocrinology 86 141149. (https://doi.org/10.1111/cen.13163)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Guan B, Welch JM, Sapp JC, Ling H, Li Y, Johnston JJ, Kebebew E, Biesecker LG, Simonds WF, Marx SJ, et al. 2016 GCM2-activating mutations in familial isolated hyperparathyroidism. American Journal of Human Genetics 99 10341044. (https://doi.org/10.1016/j.ajhg.2016.08.018)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gutmann DH, Ferner RE, Listernick RH, Korf BR, Wolters PL & Johnson KJ 2017 Neurofibromatosis type 1. Nature Reviews Disease Primers 3 17004. (https://doi.org/10.1038/nrdp.2017.4)

  • Havekes B, King K, Lai EW, Romijn JA, Corssmit EP & Pacak K 2010 New imaging approaches to phaeochromocytomas and paragangliomas. Clinical Endocrinology 72 137145. (https://doi.org/10.1111/j.1365-2265.2009.03648.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Herfarth KK, Bartsch D, Doherty GM, Wells SA Jr & Lairmore TC 1996 Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Surgery 120 966973. (https://doi.org/10.1016/S0039-6060(96)80042-0)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hernandez KG, Ezzat S, Morel CF, Swallow C, Otremba M, Dickson BC, Asa SL & Mete O 2015 Familial pheochromocytoma and renal cell carcinoma syndrome: TMEM127 as a novel candidate gene for the association. Virchows Archiv 466 727732. (https://doi.org/10.1007/s00428-015-1755-2)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Hindie E, Ugur O, Fuster D, O'Doherty M, Grassetto G, Urena P, Kettle A, Gulec SA, Pons F, Rubello D, et al. 2009 EANM parathyroid guidelines. European Journal of Nuclear Medicine and Molecular Imaging 36 12011216. (https://doi.org/10.1007/s00259-009-1131-z)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hindie E, Zanotti-Fregonara P, Tabarin A, Rubello D, Morelec I, Wagner T, Henry JF & Taieb D 2015 The role of radionuclide imaging in the surgical management of primary hyperparathyroidism. Journal of Nuclear Medicine 56 737744. (https://doi.org/10.2967/jnumed.115.156018)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Iacobone M, Carnaille B, Palazzo FF & Vriens M 2015 Hereditary hyperparathyroidism – a consensus report of the European Society of Endocrine Surgeons (ESES). Langenbeck's Archives of Surgery 400 867886. (https://doi.org/10.1007/s00423-015-1342-7)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Imai T, Uchino S, Okamoto T, Suzuki S, Kosugi S, Kikumori T, Sakurai A & Japan MENCo 2013 High penetrance of pheochromocytoma in multiple endocrine neoplasia 2 caused by germ line RET codon 634 mutation in Japanese patients. European Journal of Endocrinology 168 683687. (https://doi.org/10.1530/EJE-12-1106)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jiang S & Dahia PL 2011 Minireview: the busy road to pheochromocytomas and paragangliomas has a new member, TMEM127. Endocrinology 152 21332140. (https://doi.org/10.1210/en.2011-0052)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Jochmanova I, Yang C, Zhuang Z & Pacak K 2013 Hypoxia-inducible factor signaling in pheochromocytoma: turning the rudder in the right direction. Journal of the National Cancer Institute 105 12701283. (https://doi.org/10.1093/jnci/djt201)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jochmanova I, Zelinka T, Widimsky J Jr & Pacak K 2014 HIF signaling pathway in pheochromocytoma and other neuroendocrine tumors. Physiological Research 63 (Supplement 2) S251S262.

    • Search Google Scholar
    • Export Citation
  • Karga HJ, Karayianni MK, Linos DA, Tseleni SC, Karaiskos KD & Papapetrou PD 1998 Germ line mutation analysis in families with multiple endocrine neoplasia type 2A or familial medullary thyroid carcinoma. European Journal of Endocrinology 139 410415. (https://doi.org/10.1530/eje.0.1390410)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kepenekian L, Mognetti T, Lifante JC, Giraudet AL, Houzard C, Pinson S, Borson-Chazot F & Combemale P 2016 Interest of systematic screening of pheochromocytoma in patients with neurofibromatosis type 1. European Journal of Endocrinology 175 335344. (https://doi.org/10.1530/EJE-16-0233)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Korpershoek E, Petri BJ, Post E, van Eijck CH, Oldenburg RA, Belt EJ, de Herder WW, de Krijger RR & Dinjens WN 2014 Adrenal medullary hyperplasia is a precursor lesion for pheochromocytoma in MEN2 syndrome. Neoplasia 16 868873. (https://doi.org/10.1016/j.neo.2014.09.002)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Korpershoek E, Koffy D, Eussen BH, Oudijk L, Papathomas TG, van Nederveen FH, Belt EJ, Franssen GJ, Restuccia DF, Krol NM, et al. 2016 Complex MAX rearrangement in a family with malignant pheochromocytoma, renal oncocytoma, and erythrocytosis. Journal of Clinical Endocrinology and Metabolism 101 453460. (https://doi.org/10.1210/jc.2015-2592)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kraimps JL, Denizot A, Carnaille B, Henry JF, Proye C, Bacourt F, Sarfati E, Dupond JL, Maes B, Travagli JP, et al. 1996 Primary hyperparathyroidism in multiple endocrine neoplasia type IIa: retrospective French multicentric study. Groupe d'Etude des Tumeurs a Calcitonine (GETC, French Calcitonin Tumors Study Group), French Association of Endocrine Surgeons. World Journal of Surgery 20 808812. (https://doi.org/10.1007/s002689900123)

    • Crossref
    • 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
  • Lassen T, Friis-Hansen L, Rasmussen AK, Knigge U & Feldt-Rasmussen U 2014 Primary hyperparathyroidism in young people. When should we perform genetic testing for multiple endocrine neoplasia 1 (MEN-1)? Journal of Clinical Endocrinology and Metabolism 99 39833987. (https://doi.org/10.1210/jc.2013-4491)

    • Search Google Scholar
    • Export Citation
  • Lee JE, Curley SA, Gagel RF, Evans DB & Hickey RC 1996 Cortical-sparing adrenalectomy for patients with bilateral pheochromocytoma. Surgery 120 10641070. (https://doi.org/10.1016/S0039-6060(96)80056-0)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, Naruse M, Pacak K, Young WF Jr & Endocrine S 2014 Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 99 19151942. (https://doi.org/10.1210/jc.2014-1498)

    • Crossref