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Endocrine-Related C Guerin et al. MEN2 and non-MEN2 PHEO 25:2 T15–T28 Cancer and HPTH THEMATIC REVIEW Looking beyond the thyroid: advances in the understanding of pheochromocytoma and hyperparathyroidism phenotypes in MEN2 and of non-MEN2 familial forms

Carole Guerin1, Pauline Romanet2, David Taieb3, Thierry Brue4, André Lacroix5, Frederic Sebag1, Anne Barlier2 and Frederic Castinetti4

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

Correspondence should be addressed to F Castinetti: [email protected]

This paper is part of a thematic review section on 25 Years of RET and MEN2. The guest editors for this section were Lois Mulligan and Frank Weber.

Abstract

Over the last years, the knowledge of MEN2 and non-MEN2 familial forms of Key Words pheochromocytoma (PHEO) has increased. In MEN2, PHEO is the second most frequent ff pheochromocytoma disease: the penetrance and age at diagnosis depend on the mutation of RET. Given ff hyperparathyroidism the prevalence of bilateral PHEO (50% by age 50), adrenal sparing surgery, aimed ff multiple endocrine at sparing a part of the adrenal cortex to avoid adrenal insufficiency, should be neoplasia 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 Endocrine-Related Cancer compared with familial hypocalciuric hypercalcemia. (2018) 25, T15–T28

Introduction

The majority of the studies published on MEN2 focused outcome if undiagnosed or inappropriately treated (Wells on medullary thyroid cancer (MTC), as it represents the et al. 2013). However, in familial cases with early genetic first manifestation of the disease and can lead to a fatal diagnosis, the guidelines recommend prophylactic

10.1530/ERC-17-0266 Endocrine-Related C Guerin et al. MEN2 and non-MEN2 PHEO 25:2 T16 Cancer and HPTH

Table 1 Main characteristics of cluster 2 hereditary pheochromocytomas.

Familial PPGL with TMEM127 gene Familial PPGL with Disease Multiple endocrine neoplasia type 2 Neurofibromatosis type 1 mutation MAX gene mutation Gene RET NF1 TMEM127 MAX Chromosomal 10q11.21 17q11.2 2q11.2 14q23.3 locus Gene function proto-oncogene tumor suppressor gene tumor suppressor tumor suppressor gene gene Genetic activating mutation inactivating mutation inactivating inactivating Mechanism mutation mutation Inheritance AD AD AD AD Phenotype Multiple Endocrine Multiple Endocrine Neurofibromas (95%), Single or bilateral Bilateral PHEO, Neoplasia type 2A Neoplasia type 2B café au lait spots (90%), PHEO (30–50%); thoraco-abdominal MTC (100%), PHEO MTC (100%), iris hamartomas (90%), PGL (0–4%), renal PGL, renal (50%), primary HPTH PHEO (50%), bony lesion, skinfold cell carcinoma, oncocytoma (25%), notalgia marfanoid freckling (80%), optic C cell hyperplasia habitus, mucosal pathway tumor (15%). neuromas PHEO (0, 1–10%) Secretion Both metanephrins and normetanephrins Both metanephrins and Mainly Mainly profile normetanephrins metanephrins normetanephrins secretion secretion PHEO Rare <10% Rare <25% malignancy

AD, autosomal dominant; HPTH, hyperparathyroidism; MTC, medullary thyroid carcinoma; PHEO, pheochromocytoma; PGL, paraganglioma; PPGL, pheochromocytoma and paraganglioma. thyroidectomy leading to the absence of residual thyroid MEN2 PHEO disease (Wells et al. 2015). Thus, the chronic disease risk Epidemiology and genetics of MEN2 is the development of pheochromocytoma PHEO is the second most frequent disease in patients (PHEO), and less frequently of hyperparathyroidism with MEN2. It is usually diagnosed in the 3rd–4th decade (HPTH). The aim of this review is first to detail the main (Nguyen et al. 2001). Even if some reports mentioned characteristics and the management of MEN2 PHEO and the possibility of PHEO first, with a delayed appearance then to define the main other etiologies of hereditary of MTC, PHEO is diagnosed concomitantly or after the bilateral PHEO (Table 1). A similar review will be made diagnosis of MTC in the very large majority of cases. Imai for HPTH. and coworkers reported that 17% of their 144 MEN2 patients were actually diagnosed with PHEO before MTC Pheochromocytoma in MEN2 and non-MEN2 (Imai et al. 2013), however, calcitonin measurement familial forms was not systematically performed, nor, obviously PHEO are neuroendocrine tumors arising from adrenal thyroidectomy, and it is thus not sure that these patients medulla cells. Paragangliomas (PGL) originate form indeed had normal C-cells at the time of PHEO diagnosis. sympathetic or parasympathetic paraganglia; they have The penetrance and age at diagnosis of PHEO in rarely been reported in MEN2 patients (less than 1% MEN2 seems to be dependent on the RET mutation. in our series of 1210 patients with MEN2) (Castinetti For instance, Imai and coworkers reported that the et al. 2014), but constitute a unique entity together penetrance of PHEO was 52% by age 50 years in with PHEO in other hereditary forms. Management codon 634 RET mutation carriers, while it was 36% at of pheochromocytoma requires highly-specialized last follow-up in patients with mutations other than teams: pre-operative management should be aimed at codons 634 and 918 (Imai et al. 2013). In our large normalizing blood pressure and heart rate, based on series based on 563 individuals presenting with MEN2 alpha-adrenergic receptor blockers, high sodium diet PHEO, while 60% patients with 634-RET mutations had and fluid intake, 7–14 days before surgery, with a careful at least one PHEO at last follow-up (median age at first monitoring of blood pressure, as stated by the Endocrine diagnosis, 35 years), less than 20% of patients carrying Society guidelines (Lenders et al. 2014). with RET exon 10 mutations presented with PHEO at

http://erc.endocrinology-journals.org © 2018 Society for Endocrinology https://doi.org/10.1530/ERC-17-0266 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/25/2021 10:48:16PM via free access Endocrine-Related C Guerin et al. MEN2 and non-MEN2 PHEO 25:2 T17 Cancer and HPTH age 35 years (Castinetti et al. 2014). A strong genotype/ multifocal in the same adrenal gland (Korpershoek et al. phenotype correlation thus exists for PHEO penetrance 2014). Symptoms of catecholamine oversecretion can be in MEN2 patients. However, we recently reported that already seen at the stage of hyperplasia. The development the penetrance of PHEO in MEN2 was variable depending of PHEO in MEN2 is usually progressive, and bilateral on the geographic area, with an age at first diagnosis of PHEO are not always synchronous: metachronous PHEO PHEO significantly higher in South America than that have been reported in up to 25% cases after a mean period in Europe (Castinetti et al. 2017). The American Thyroid of 5–10 years (Thosani et al. 2013, Castinetti et al. 2014), Association (ATA) guidelines recommended screening requiring a prolonged follow-up after the first surgery. for PHEO beginning at 11 years for children in the ATA- Positive diagnosis is based on increased plasma or urinary high and highest risk (RET codons 634, 883 and 918) and fractionated metanephrine and normetanephrine (Bravo 16 years in the ATA-moderate risk (all the other codons) & Tagle 2003, Eisenhofer et al. 2011). Imaging should be (Wells et al. 2015). Of note, one case report described the performed only when biochemistry becomes positive. occurrence of PHEO in an 8-year-old boy carrying a 634 RET codon mutation (Rowland et al. 2013). Imaging Interestingly, in MEN2, patients within the same Once the biochemical diagnosis is established, the PHEO family, i.e. carrying the same mutation and theoretically needs to be localized. The commonest approach for exposed to the same environment, can present a different localizing PHEO is to perform anatomical imaging studies. penetrance of PHEO (absence, unilateral or bilateral): Although CT is a radiation-ionizing diagnostic imaging, it this might be due to modifying genes as recently provides a higher resolution than MRI enabling detection suggested to explain at least partly the difference of MTC of unique and multiple PHEO including those that aggressiveness in patients with MEN2A compared to can coexist within the same glands. Most importantly, MEN2B (Oczko-Wojciechowska et al. 2017). Siqueira and anatomical imaging may also guides surgeons toward coworkers had already shown that RET polymorphisms the most appropriate surgical strategy (total vs subtotal). had an influence on the prevalence of MEN2 PHEO Therefore, the follow-up of MEN2-related PHEO should (Siqueira et al. 2014). For instance, the presence of two not be delayed beyond the scheduled time for subtotal RET variants among L769L, S836S and G691S/S904S adrenalectomy (cortical-sparing surgery). Many of the was associated with an increased risk for early PHEO MEN2 patients do not need any specific functional development (Siqueira et al. 2014). imaging since the tumors are almost always confined to The outcome of MEN2 PHEO is usually good in the adrenal gland and the likelihood of metastasis is very specialized MEN/endocrine referral centers. Thosani and small. Currently, several specific radiopharmaceuticals coworkers reported only 2 deaths out of 84 patients, (123I-MIBG, 18F-FDA, 18F-FDOPA PET and 68Ga-DOTA- because of PHEO with hypertensive crises and autopsy somatostatin analogs) are available. The main advantage diagnosis; however, the diagnostic procedure had been of 18F-FDOPA compared to other radiopharmaceuticals is performed in the 1960s, and such events now appear to the absence or faintly uptake by normal adrenal glands. be very rare in the modern era of PHEO management On 18F-FDOPA PET/CT, uptake should be considered as (Thosani et al. 2013). In our series, 5 deaths (<1%) pathological only in cases of adrenal uptake more intense were due to PHEO, 4 because of hypertensive crises in than the liver with concordant enlarged gland. 18F-FDOPA undiagnosed patients and 1 because of diffuse PHEO PET/CT can also detect residual MTC in patients with metastases (Castinetti et al. 2014). persistant hypercalcitoninemia (Timmers et al. 2009, Havekes et al. 2010, Taieb et al. 2012, Castinetti et al. 2015, Diagnosis Shamim et al. 2015). 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 Treatment the time PHEO was diagnosed (Castinetti et al. 2014). Adrenal surgery is the only available treatment: it should Systematic screening should thus be performed regularly be done before thyroid surgery in case of concomitant even in the absence of clinical signs suggestive of PHEO. diagnosis of MTC and PHEO. Adrenalectomy should From a pathophysiological viewpoint, adrenomedullary be performed in PHEO as soon as the biology becomes hyperplasia precedes PHEO, and PHEO is frequently positive and/or in patients regularly followed for a

http://erc.endocrinology-journals.org © 2018 Society for Endocrinology https://doi.org/10.1530/ERC-17-0266 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/25/2021 10:48:16PM via free access Endocrine-Related C Guerin et al. MEN2 and non-MEN2 PHEO 25:2 T18 Cancer and HPTH size cutoff >1 cm. Bilateral adrenalectomy should only in asymptomatic carriers. Being able to perform an early be performed when synchronous bilateral PHEO are diagnosis of PHEO is mandatory to allow the surgeon to diagnosed (Lairmore et al. 1993). Interestingly, despite the get the possibility to perform adrenal-sparing surgery, screening procedures usually leading to smaller PHEO at and avoid the risk of permanent post-surgical adrenal the time of surgery (compared with sporadic PHEO), the insufficiency in patients with bilateral PHEO. risk of hypertensive episodes during resection is identical: a similar pharmacological preparation predominantly with alpha blockers should thus be performed before Non-MEN2 familial forms: the cluster 2 genes surgery (Scholten et al. 2011b). Transcriptomic studies performed over recent years The question remains on the role of adrenal sparing established a clustered classification for PHEO/PGL surgery when bilateral adrenalectomy is required in such (reviewed in Gimenez-Roqueplo et al. 2012, Vicha et al. patients. We and others have reported the excellent short- 2013). Cluster 1 is characterized by activation of the term outcomes of such an approach: the idea of adrenal- hypoxia-angiogenesis pathway despite normoxia: It sparing surgery is to take off the PHEO while maintaining includes SDH- and VHL-related tumors. The hypoxia- 1/3rd–1/4th of the gland to allow maintenance of a inducible factor (HIF) is abnormally stabilized due to an normal cortisol and aldosterone function. Out of 552 impairment in the VHL-mediated degradation system patients operated, adrenal sparing surgery was performed and induces angiogenesis, promoting the development in 114 (20.6%). Normal cortisol function was reported in of PHEO and PGL (Eisenhofer et al. 2004, Barontini & 57% of patients operated for bilateral PHEO with at least Dahia 2010, Jochmanova et al. 2013, 2014). Cluster 2 1 sparing surgery (Castinetti et al. 2014). The results were includes genes which mutations lead to dysregulation of quite the same as those for Grubbs and coworkers with intracellular signaling pathways (PI3K/AKT, MAPK/ERK 58% of normal glucocorticoid function in 33 patients kinase), triggering tumorigenesis: RET and NF1 activate operated with adrenal sparing surgery (Grubbs et al. PI3K/AKT/mTOR and RAS/RAF/MAPK signaling pathways; 2013). The main risk of adrenal sparing surgery is PHEO TMEM127 enhances mTOR activity; MAX modifies recurrence: indeed, complete adrenal medulla resection the MYC-MAX-MXD1 network connected with mTOR is technically impossible, and the risk of recurrence in pathway. Recently, based on mRNA analysis, Fishbein and this germinal disease is thus very high: while we had 3% coworkers subdivided the whole group of PHEO/PGL in 4 risk of recurrence after 10 years of follow-up, other series different entities: Wnt-altered pathway, kinase signaling reported 1–11% risk of recurrence after a mean follow-up pathway, pseudohypoxia pathway and what they called of 6–10 years after surgery (reviewed in Castinetti et al. cortical admixture (Fishbein et al. 2017). Interestingly, 2016). It is likely that this risk will increase dramatically germline mutations in MAX occurred in this specific the longer the duration of follow-up. Prolonged follow-up subgroup and not in the Cluster 2 class (Fishbein et al. is thus required in these patients. As there is only a 2017). The main pathways involved in PHEO pathogenesis very low 1–4% risk of malignancy for MEN2 PHEO (Lee are depicted in Fig. 1 (data from Dahia 2014). et al. 1996), we suggest that this procedure should be For this review, we will thus specifically focus on the systematically considered in all patients with MEN2 genes classified in the cluster 2, but we will also include PHEO. Of note, adrenal sparing surgery has an inherent MAX. Cluster 1 genes will not be discussed. Of note, the limit due to the pathophysiology of MEN2 as PHEO are differential diagnosis with MEN2 for cluster 2 is mainly frequently multifocal in the same gland, which can make theoretical as normal calcitonin level at the time of PHEO sparing surgery impossible, because of the impossibility diagnosis will rule out the possibility of MEN2. 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, NF1 or in some very experienced centers, by another partial Neurofibromatosis type 1 (NF1 or Von Reklinghausen adrenalectomy (Brauckhoff et al. 2004). disease) is an autosomal dominant disease due to In summary, PHEO will become the most prevalent mutations of NF1, a tumor suppressor gene. NF1 is mainly disease of MEN2 given the fact that young familial cases characterized by neurofibromas, café au lait spots, optic are treated by prophylactic thyroidectomy. The majority pathway tumors, iris hamartomas, bony lesions and of the patients will be asymptomatic at the time of skinfold freckling (reviewed in Gutmann et al. 2017). PHEO diagnosis, which implies a regular biological follow-up occurs in only 0.1–10% of cases; it is however one the most

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). frequent etiology of hypertension in patients with NF1 were identified in 17% of the patients, while metastases (20–50% cases). This low prevalence explains why only were reported in 7%. The majority of patients (91%) had case reports and small series have been reported in the both metanephrine and normetanephrine secretion at literature. Two small studies suggested that NF1 PHEO size diagnosis (Gruber et al. 2017). was usually smaller at the time of diagnosis despite the fact PHEO screening in NF1 patients should be based on that the diagnosis was made at a later age than sporadic biology every 3 years beginning at age 10–14 years. In PHEO (Shinall & Solorzano 2014, Moramarco et al. 2017). contrast, systematic NF1 genetic screening in patients with This likely explains why Kepenikian and coworkers an apparently sporadic PHEO is not recommended, unless recently showed that the majority of the patients with there are clinical signs suggestive of neurofibromatosis NF1 PHEO were not symptomatic at the time of diagnosis, (Bausch et al. 2006). Optimal management of NF1 PHEO emphasizing the need for systematic biological screening is based on adrenalectomy (Gruber et al. 2017). 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 TMEM127 reported: the median age at diagnosis was 41 years (range Germline TMEM127 mutations were first identified as 14–67); the median size of PHEO at the time of diagnosis an etiology of PHEO seven years ago (Qin et al. 2010). was 3.4 cm (range 0.8–9.5). Bilateral pheochromocytomas TMEM127 mutations prevalence is estimated to be around

2% (1.7% out of 1676 patients tested with PHEO and PGL) has been reported for TMEM127 mutations (Hernandez (Abermil et al. 2012, Bausch et al. 2017). TMEM127 is a et al. 2015). Up to now, roughly 150 patients with tumor suppressor, encoding a transmembrane protein TMEM127 mutations have been reported in the literature. localized in several intracellular organelles (Jiang & Dahia For a detailed list of TMEM127 variants reported in the 2011). Mutations of TMEM127 lead to a drastic decreased literature, please refer to Supplementary Table 1 (Qin et al. function of the protein with an anarchic distribution into 2010, Neumann et al. 2011, Abermil et al. 2012, Takeichi the cytoplasm, and dysregulate mTORC1 signaling complex et al. 2012, Elston et al. 2013, Rattenberry et al. 2013, activation. In patients with TMEM127 mutations, the age Curras-Freixes et al. 2015, Toledo et al. 2015, Patocs et al. at diagnosis of PHEO was highly variable from 20 to more 2016, Bausch et al. 2017). 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 MYC associated factor X (MAX) at last follow-up. One third of the patients with TMEM127 MAX mutations were first identified as a cause of PHEO mutations had a sporadic appearing benign PHEO. 6 years ago (Comino-Mendez et al. 2011). MAX, a Interestingly, a history of PHEO was observed in only a tumor suppressor gene, is a component of the MYC- quarter of familial cases, suggesting a low penetrance, MAX-MXD1 network of basic helix-loop-helix leucine even if the late age at first diagnosis of PHEO might have zipper transcription factors, regulating cell proliferation, biased these data because of an insufficient follow-up differentiation and apoptosis. It is likely that MAX acts as period (Qin et al. 2010, Yao et al. 2010). Neumann and a negative regulator of the network: germline mutations coworkers expanded the phenotype one year later, by of MAX disable its repressing activity and lead to MYC describing the occurrence of PGL in 2 patients (1 with dysregulation and cancer predisposition (Cascon & multiple head and neck PGL, 1 with retroperitoneal extra- Robledo 2012). Twelve cases were reported by Comindo- adrenal tumor), leading to a prevalence of PGL of 4% Mendez and coworkers: age at diagnosis ranged from 17 to in this series of 48 patients (Neumann et al. 2011). No 47 years old; the majority of the patients were presenting patient had a malignant disease (Neumann et al. 2011). with bilateral PHEO at diagnosis, and 3 patients had Finally, the phenotype has been recently completed metastatic PHEO at last follow-up (Comino-Mendez et al. with multifocal PHEO and (nodular) adrenal hyperplasia 2011). These characteristics were confirmed by a second (<1 cm) preceding and/or coexisting with PHEO (Toledo prevalence study in a series of 1694 patients with PHEO et al. 2015). Abermil and coworkers reported a prevalence and no mutation in other susceptibility genes: 16 MAX of 0.9% (n = 6 patients) of TMEM127 mutations in a large mutations were identified in 23 index patients (prevalence, cohort of 642 unrelated patients with negative testing 1.1%). The majority of them had bilateral PHEO, and for classical genes of PHEO and paraganglioma (Abermil 16% had additional thoraco-abdominal PGL. Two et al. 2012). The overall characteristics were comparable patients were metastatic at last follow-up. The secretion with a variable age at diagnosis, a sporadic presentation profile was mainly high secretion of normetanephrine in half of the patients, bilaterality in half of the patients, with normal or moderately increased metanephrine. Of and the lack of paraganglial tumor. In this series as in note, 2 patients presented a renal carcinoma and a renal the previous one, all the 5 patients with data available oncocytoma (Burnichon et al. 2012). This finding was on secretion were presenting with higher metanephrine recently confirmed in the first study reporting a large and normetanephrine. Finally, age-related penetrance of genomic deletion of MAX in 3 siblings presenting with TMEM127-PHEO was evaluated in 0% at 0–20 years, 3% bilateral PHEO (n = 2) and a renal oncocytoma (n = 1). This at 21–30 years, 15% at 31–40 years, 24% at 41–50 years could suggest that MAX also acts as a suppressor gene and 32% at 51–65 years (Toledo, JCEM, 2015). Clinical for renal oncocytomas (Korpershoek et al. 2016), and screening of TMEM127 mutation carriers should start at change the way to follow such patients (with a systematic 20 years of age, while genetic screening of at risk individuals screening for renal cancers on a long-term basis?). Up to should be performed before this age (Toledo et al. 2015). now, roughly 60 patients with MAX mutations have been Of note, large TMEM127 gene deletions or duplications reported in the literature. For a detailed list of cases of have never been reported in any patient (Abermil et al. MAX variants reported in the literature, please refer to 2012). Optimal management of TMEM127 PHEO is based Supplementary Table 2 (Comino-Mendez et al. 2011, 2015, on adrenalectomy. Interestingly, the association between Burnichon et al. 2012, Peczkowska et al. 2013, Welander pheochromocytoma/paraganglioma and renal tumors et al. 2014, Bausch et al. 2017, Romanet et al. 2017).

Hyperparathyroidism in MEN2 and non-MEN2 unknown, but FIHP has been reported to be associated familial forms with mutations in the MEN1, CaSR, CDC73 and more recently GCM2 genes (Table 2) (based on (Miedlich et al. Primary HPTH is a rather frequent disease, with an 2003, Thakker et al. 2012, Iacobone et al. 2015, Guan et al. incidence of 1 per 1000, including 5–10% of hereditary 2016,Vargas-Poussou et al. 2016). etiology. These genetic etiologies include isolated primary hyperparathyroidism (such as in familial hypocalciuric hypercalcemia) and syndromic HPTH, among which MEN2 hyperparathyroidism RET mutations. Familial isolated HPTH (FIHP; OMIM 145000) is defined as autosomal dominant hereditary Epidemiology and genetics HPTH without any other associated endocrinopathies. In HPTH penetrance is lower than MTC and PHEO in MEN2. the majority of families, the genetics background remains The prevalence is estimated to be 20% in MEN2A cases

Table 2 Etiologies of hereditary HPTH and phenotypic descriptions.

Syndromic hereditary HPTH Multiple endocrine Disease neoplasia type 1 HPTH – jaw tumor syndrome Multiple endocrine neoplasia type 4 Gene MEN1 CDC73 CDKN1B Gene function tumor suppressor tumor suppressor gene tumor suppressor gene gene Chromoso- mal locus 11q13.1 1q31.2 12p13.1 Inheritage AD AD AD Phenotype Primary HPTH (90%), Primary HPTH (95%), parathyroid Primary HPTH (81%), pituitary adenoma Neuroendocrine carcinoma (21%), fibro-osseous (46%), gastric and bronchic carcinoid duodenopancreatic tumour (30%), renal tumor (13%), tumours, gastropancreatic tumour, tumor (30–70%), uterine tumour (57% of females) adrenal tumour pituitary adenoma (30–40%), adrenal tumour (40%) Prevalence 1/30,000 Unknown Unknown Median age of HPTH 20–25 years 27 years Unknown Disease Familial Isolated Primary HPTH (FIPH) Gene GCM2 MEN1 CaSR CDC73 Gene function proto-oncogene tumor suppressor CaSR signaling tumor suppressor gene no identified gene pathway gene Chromoso- mal locus 6p24.2 11q13.1 3q21.1 1q31.2 Inheritage AD AD AD AD AD Phenotype Isolated primary HPTH Isolated primary Isolated primary Isolated primary HPTH Isolated HPTH HPTH primary HPTH Prevalence Unknown 18% of FIPH Unknown 7% of FIPH Median age of HPTH Unknown Unknown Unknown Unknown Disease Neonatal severe HPTH Differential diagnosis FHH1 FHH2 FHH3 Gene CaSR CaSR GNA11 AP2S1 Gene function CaSR signaling CaSR signaling CaSR signaling CaSR signaling pathway pathway pathway pathway Chromoso- mal locus 3q21.1 3q21.1 19p13.3 19q13.3 Inheritage AR or AD AD AD AD Phenotype Servere Longlife Longlife Longlife hypercalemia, relative hypercalcemia, letal hypercalemia, hypercalemia, hypocalciuremia, normal or mild without parathyroi- relative hypo- relative hypo- elevated PTH dectomy calciuremia, calciuremia, normal or mild normal or mild elevated PTH elevated PTH Prevalence Unknown 1/10,000 to Unknown Unknown 1/100,000 Median age of HPTH Neonatal Unknown Unknown Unknown

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

(while it is always absent in MEN2); some series even diagnosis, imaging can be made to help the surgeon, reported a much lower prevalence of 5% in patients with even if multiglandular disease is present in the majority RET mutations (Frank-Raue et al. 2011, Elisei et al. 2012, of cases, and bilateral neck compartments exploration is Machens et al. 2013). In MEN2A, hyperparathyroidism usually mandatory. seems to be more frequently associated with 634-RET mutations than other codons (Kraimps et al. 1996, Karga Imaging et al. 1998, Raue & Frank-Raue 2009, Valdes et al. 2015). When HPTH is diagnosed in a MTC patient, minimally Twenty years ago, Schuffenecker and coworkers had invasive parathyroidectomy approach is not a reported that the prevalence of hyperparathyroidism did recommended surgical approach for HPTH since bilateral not differ between patients with C634R or other 634 codon cervicotomy is required for total thyroidectomy. In mutations; however, there was a wide intervariability this situation, neck ultrasound enables preoperative among families, with a prevalence varying from 9 to staging of MTC and localization of parathyroid lesions. 40% (again suggesting the involvement of modifying or The role of radionuclide imaging is more limited since environmental factors) (Schuffenecker et al. 1998). ectopic or supernumerary glands are very rare and most Parathyroid hyperplasia precedes the development of of the lesions can be removed via the cervical route. By adenoma formation, but the hyperplasic stage can lead to contrast, when HPTH is diagnosed after thyroidectomy hypercalcemia (Mete & Asa 2013). Moreover, hyperplasia for MTC, preoperative localizing studies are needed for and adenoma can coexist in several glands at the time of directing focused approaches (concordance between diagnosis, in favor of an asynchronous development of the neck ultrasound and PS for the same abnormality). parathyroid disease in MEN2. This means that at a given The optimal protocol should use the 99mTc-MIBI/123I time point, some glands can still be normal, and recurrence subtraction protocol with pinhole acquisition (Hindie will happen after a more or less prolonged period of time et al. 2009, 2015). The use of 4-dimensional computed after partial parathyroidectomy. In contrast, parathyroid tomography (4D-CT) for parathyroid imaging has been carcinoma has never been reported in MEN2. In sporadic reported but increases radiation exposure to the patient hyperparathyroidism, patients are usually older, with a (Philip et al. 2008). 18F-fluorocholine PET/CT was found mean age at diagnosis close to 60 years, and they have only to be very sensitive and specific in patients with sporadic 1 pathologic parathyroid gland. In contrast, the mean age primary HPTH or renal HPTH and would need to be at diagnosis of hyperparathyroidism in MEN2 is usually evaluated in the setting of MEN2 patients, especially in close to 40 years (Kraimps et al. 1996, Schuffenecker et al. cases with recurrent HPTH and negative or discordant 1998, Machens et al. 2013). imaging findings. MTC precedes hyperparathyroidism, even if some rare cases depicted early diagnosis of hyperparathyroidism (Mian et al. 2009, Magalhaes et al. 2011). MEN2 diagnosis Management is thus rarely made after an isolated diagnosis of primary In MEN2, management raises the question of the extent hyperparathyroidism. The majority of the patients of parathyroidectomy, which should be performed when are asymptomatic at the time of diagnosis (Carling & HPTH is diagnosed in the preoperative workup of MTC: Udelsman 2005), emphasizing the need for a systematic total parathyroidectomy, total parathyroidectomy with yearly calcium work-up in patients with MEN2, as stated autotransplantation or selective parathyroidectomy with by the ATA guidelines. removal of macroscopically abnormal glands (Herfarth et al. 1996, Yoshida et al. 2009, Scholten et al. 2011a). Diagnosis and screening Total parathyroidectomy without autotransplantation The ATA recommends to begin screening by age 8 years will lead to permanent hypoparathyroidism, a condition in patients with MEN2A, and to screen on a yearly not always easy to handle. Recently, Moley and coworkers basis for biology suggesting hyperparathyroidism in reported their experience of the management of asymptomatic carriers whatever the codon (Wells et al. parathyroid glands during preventive thyroidectomy in 2015). The diagnosis procedure is the same as the one patients with MEN2 (Moley et al. 2015). They did not performed in sporadic hyperparathyroidism, with at least notice any difference between preventive thyroidectomy, calcium level and albumin and then PTH, phosphate and central neck dissection, total parathyroidectomy and urinary calcium (Elisei et al. 2012). In case of positive autotransplantation to the forearm or to the neck,

http://erc.endocrinology-journals.org © 2018 Society for Endocrinology https://doi.org/10.1530/ERC-17-0266 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/25/2021 10:48:16PM via free access Endocrine-Related C Guerin et al. MEN2 and non-MEN2 PHEO 25:2 T23 Cancer and HPTH compared to preventive thyroidectomy attempting (Singh Ospina et al. 2014). In parallel, the MD Anderson to preserve the parathyroid glands in situ with an Cancer Center also identified 2 patients in a series of intact vascular pedicle (autotransplantation only if the 291, leading to a prevalence of 0.8%. This may not be parathyroid did not seem viable or could not be preserved different from the prevalence of parathyroid carcinoma intact): permanent hypoparathyroidism was not in patients with sporadic primary hyperparathyroidism significantly different between both groups (6% vs 1%, (0.74) (Christakis et al. 2016). The pathological diagnosis P = 0.1) (Moley et al. 2015). Of note, it is not recommended of parathyroid carcinoma is usually difficult, and currently to perform systematic parathyroidectomy in based on invasion of the thyroid, the laryngeal nerve patients with MEN2 requiring thyroid surgery for MTC or other neck structures. Treatment is usually based (either prophylactic or not), and still normal PTH and on parathyroidectomy. The main risk is biological calcium level. In contrast, when HPTH is diagnosed after recurrence, rather than systemic metastasis, requiring thyroidectomy, a tailored parathyroidectomy should be further surgery or the use of cinacalcet (Sensipar), which performed based, as previously stated, on an exhaustive is marketed in this specific indication Singh( Ospina et al. imaging workup. 2014, Christakis et al. 2016). Initial surgery mostly relies on subtotal rather than total parathyroidectomy with autotransplantation. In Non-MEN2 hyperparathyroidism recurrent cases, parathyroid surgery should be repeated Multiple endocrine neoplasia type 1 after a complete imaging workup to identify the cause (MEN1) hyperparathyroidism (hyperplasia of the parathyroid remnant, supranumerary/ One objective of this review is to discuss the novelties of ectopic glands) and allow to perform a tailored approach in non-MEN2 familial forms of hyperparathyroidism. We experienced surgical hands, repeat surgery usually leads to thus will not discuss in detail MEN1, but will specifically normal calcium levels (when a piece of parathyroid gland focus on studies published during the last 3–4 years. is maintained) or to hypoparathyroidism. When surgery Hyperparathyroidism is the earliest and most common is impossible, an alternate medical treatment is possible. feature of MEN1, with a median age at diagnosis of Giusti and coworkers recently reported their experience 20–25 years, and a prevalence of almost 100% of cases with the use of cinacalcet therapy in patients with MEN1 by age 50–60 years. An epidemiological overview of (Giusti et al. 2016). Cinacalcet is able to bind the calcium MEN1 patients diagnosed before age 21 years showed sensor receptor and increases its sensitivity to extracellular that only 56% of the patients presented with primary calcium: this leads to decreased levels of PTH and calcium. hyperparathyroidism as the initial occurring disease in In this 12-month multicenter prospective, open-label, MEN1. The first symptoms appeared before 10 years in non-comparative trial performed in 33 patients with 14% of cases, and before 5 in 3% of cases. This emphasizes MEN1 (22 with contra-indication or refusal to surgery the need for genetic testing when any of the disease as a first line treatment, 11 with contra-indications to listed as potentially due to MEN1 occurs in a young surgery in a context of recurrent hyperparathyroidism), patient (Goudet et al. 2015). MEN1 genetic screening cinacalcet was able to normalize calcium level in 89% should be performed in any patient with primary of the patients at the end of the study, with 30 or 60 mg hyperparathyroidism manifestations occurring before age cinacalcet daily. Five patients were excluded because of 30 years or in any patient with multiglandular disease bad tolerance to the drug, not allowing to adjust the dose whatever the age (Thakker et al. 2012, Lassen et al. 2014). of cinacalcet. Of note, no significant change was observed The natural history of hyperparathyroidism in in terms of PTH or urinary calcium at the end of the study MEN1 is similar to the one reported for MEN2, with (Giusti et al. 2016). an asynchronous disease (adenoma, hyperplasia on one or several glands) (Mete & Asa 2013). Interestingly, Multiple endocrine neoplasia type 4 (MEN4) parathyroid carcinoma, though rare, has been reported MEN1-like syndrome occurs in 5–10% patients without in patients with MEN1, without certainty that the menin mutations. A subgroup of these patients (roughly carcinoma was specific to the menin status. In a 2%) present with CDKN1B (p27) mutations. Identification series of 348 patients with MEN1 followed in a single of p27 mutations were based on a naturally occurring tertiary care center (the Mayo Clinic), a prevalence of MEN1 rat model (MENX) presenting with an 8 bp 0.28% (1 case) of parathyroid carcinoma was reported homozygous frameshift insertion leading to a premature

http://erc.endocrinology-journals.org © 2018 Society for Endocrinology https://doi.org/10.1530/ERC-17-0266 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/25/2021 10:48:16PM via free access Endocrine-Related C Guerin et al. MEN2 and non-MEN2 PHEO 25:2 T24 Cancer and HPTH stop codon in p27 (Pellegata et al. 2006). A small number The peculiar case of familial of patients with heterozygous p27 mutations have been hypocalciuric hypercalcemia reported since then, characterized by a wide variability Type 1, 2 and 3 familial hypocalciuric hypercalcemia (FHH) in all other diseases classically occurring in MEN1. are due to an abnormal inactivation of the calcium sensor Primary hyperparathyroidism, in contrast, was present receptor signaling pathway. Biological workup usually in all published cases, with an identical multiglandular shows hypercalcemia, unsuppressed PTH level (mostly involvement (Agarwal et al. 2009). Interestingly, the normal) and not-increased calciuria (low or normal). V109G p27 variant has been reported as responsible for Basically, any biological phenotype can be seen (Vargas- modifying the natural history of parathyroid involvement Poussou et al. 2016). Calcium sensor receptor gene is located in MEN1, based on a cohort of 100 patients paired with in 3q21.1, encoding for the calcium sensor receptor, a 855 controls: V109G variant was associated with a more transmembrane G protein-coupled receptor. FHH type 1 is frequent multiglandular involvement at diagnosis (3–4 vs due to inactivating mutations of CASr, FHH2 to inactivating 1–2 glandular disease) (Longuini et al. 2014). GNA11 mutations and FHH3 to mutations of AP2S1, involved in calcium sensor endocytosis. FHH usually leads Hyperparathyroidism-Jaw tumor (HPT-JT) syndrome to parathyroid hyperplasia, even if some operated patients HPT-JT is defined by the association of primary actually presented a true parathyroid adenoma. hyperparathyroidism, due to a single or multiple parathyroid adenoma or a parathyroid carcinoma (30% cases), and a Perspectives and conclusions fibro-osseous jaw tumor (30% cases). Uterine or kidney tumors have also been described as associated with this MEN2 is now a well-characterized disease; while original syndrome. Of note, primary hyperparathyroidism can be descriptions were almost exclusively focusing on MTC, isolated at diagnosis, and the penetrance of other diseases is reports published over the last 10 years provide more incomplete. Differentiating between MEN1 and HPT-JT can insights into the pathophysiology, diagnosis and thus be challenging in case of isolated hyperparathyroidism management of PHEO, and to a lower extent, HPTH. and should lead to genetic testing of both menin and Both diseases are characterized by a usually benign tumor CDC73. HPT-JT is due to mutations of CDC73 (HRPT2) profile preceded by a hyperplasic stage. Management of tumor suppressor gene, transmitted as an autosomal such tumors should thus be aimed at curing the disease dominant trait (Carpten et al. 2002). CDC73 mutations while preserving an optimal quality of life (partial lead to the loss of expression of parafibromin, a nuclear parathyroidectomy, partial adrenal surgery for instance, protein involved in chromatin remodeling and histone should be systematically considered in such patients). modification (reviewed in Thakker 2016). Bricaire and Future studies should be aimed at better exploring the coworkers reported the characteristics of 20 index patients phenotypes (with the help of large-scale international with a germinal HRPT2 abnormality: mean age at diagnosis networks) and understanding the wide variability was close to the one reported for MEN1 (23 years), but presented by the patients in terms of age at diagnosis, calcium level at diagnosis was higher (mean, 3.19 mmol/L) asynchronous disease, as this individualized approach (Bricaire et al. 2013). Interestingly, a large deletion of HRPT2 will help tailoring the treatment for each patient. was observed in a third of the cohort patients (Bricaire In non-MEN2 familial forms of PHEO and HPTH, the et al. 2013). Management of HPTH in HPT-JT is based on genetic spectrum has drastically changed over the last parathyroidectomy with bilateral neck compartments 10 years, with an increasing rate of new identified genetic exploration, given the possible multiglandular and etiologies (especially in PHEO). Interestingly, some of these potential malignant nature of the disease. In contrast with etiologies have also been linked to renal carcinogenesis, sporadic primary hyperparathyroidism, follow-up should and this will be something to take into account when be prolonged on a long-term basis to detect recurrence following patients on a long-term basis. New genes (observed in up to 80% of operated patients) requiring a are to be identified as recently shown by Fishbein and more aggressive parathyroid surgery (Sarquis et al. 2008). coworkers: for instance, fusion genes involving MAML3, Interestingly, somatic HRPT2 mutations have also been that have been reported in other tumor types, might play detected in sporadic parathyroid carcinomas, arguing for a role in the pathogenesis of hereditary PHEO (Fishbein a role of CDC73 mutations in the overall prognosis of et al. 2017). In the future, next-generation sequencing parathyroid disease (Shattuck et al. 2003). approaches will likely lead to focus on different issues,

http://erc.endocrinology-journals.org © 2018 Society for Endocrinology https://doi.org/10.1530/ERC-17-0266 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/25/2021 10:48:16PM via free access Endocrine-Related C Guerin et al. MEN2 and non-MEN2 PHEO 25:2 T25 Cancer and HPTH by questioning about the pathogenicity of variants of Bausch B, Schiavi F, Ni Y, Welander J, Patocs A, Ngeow J, Wellner U, unknown significance. Moreover, for new genes such Malinoc A, Taschin E, Barbon G, et al. 2017 Clinical characterization of the pheochromocytoma and paraganglioma susceptibility genes as MAX and TMEM127, only little is known about the SDHA, TMEM127, MAX, and SDHAF2 for gene-informed prevention. natural history of PHEO and extra-adrenal features. Large- JAMA Oncology 3 1204–1212. 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Received in final form 30 August 2017 Accepted 4 September 2017 Accepted Preprint published online 5 September 2017