- Email: [email protected]
Hyperparathyroidism in multiple endocrine neoplasia type 2A syndrome. Surgical and genetic implications
416
Scientific letters / Med Clin (Barc). 2016;146(9):414–417
In conclusion, previous studies on the effectiveness of liraglutide conducted in real life-scenarios in Europe and the USA have shown liraglutide to be superior to exenatide, sitagliptin, and insulin glargine with respect to reductions in HbA1c and weight loss. In addition, some of the predictors of a better response seem to be younger age, shorter duration of T2D, and higher weight at baseline. Based on a population of patients followed for more than 2 years, we extend the list of predictors by adding female gender, insulin naïve, and absence of the need for insulin during follow-up. Financial and competint interest disclosure This work was supported by Novo Nordisk. The authors have no other relevant affiliations, financial involvement or financial conflict with the subject matter discussed in the manuscrit. The authors take full responsibility for this paper but are grateful to Manuela Rubio for providing writing assistance in the preparation of this manuscript. References 1. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38:140–9. 2. Barnett AH. The role of GLP-1 mimetics and basal insulin analogues in type 2 diabetes mellitus: guidance from studies of liraglutide. Diabetes Obes Metab. 2012;14:304–14. 3. Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009;32:84–90.
Hyperparathyroidism in multiple endocrine neoplasia type 2A syndrome. Surgical and genetic implications夽 Hiperparatiroidismo en el síndrome de neoplasia endocrina múltiple tipo 2A. Implicaciones terapéuticas y genéticas Dear Editor, Managing hyperparathyroidism (HPT) in multiple endocrine neoplasia (MEN) 2A syndrome is controversial. It is a rare disease and few studies are available, most of them old, multicentre, and with a limited number of patients. The treatment of choice has traditionally been the subtotal or total parathyroidectomy.1 However, multiglandular involvement is not synchronous. Therefore, some authors suggest a less aggressive treatment.2–5 On the other hand, recent studies have shown that some mutations may have a more aggressive symptomatology,6 so treatment might also have a genetic involvement. A retrospective analysis has been conducted with 135 patients with MEN 2A syndrome in a tertiary hospital, including those operated of HPT, excluding patients without follow-up. Clinical and epidemiological variables, treatment, postoperative complications and persistent or recurrent HPT have been analyzed. Statistics: descriptive, 2 test when possible and Fisher exact test in other cases. 夽 Please cite this article as: Febrero B, Rodríguez JM, Ríos A, Parrilla P. Hiperparatiroidismo en el síndrome de neoplasia endocrina múltiple tipo 2A. Implicaciones terapéuticas y genéticas. Med Clin (Barc). 2016;146:416–417.
4. Nyeland ME, Ploug UJ, Richards A, Carcia Alvarez L, Demuth D, Muthutantri A, et al. Evaluation of the effectiveness of liraglutide and sitagliptin in type 2 diabetes: a retrospective study in UK primary care. Int J Clin Pract. 2015;69: 281–9. 5. Fadini GP, Simioni N, Frison V, Dal Pos M, Bettio M, Rocchini P, et al. Independent glucose and weight-reducing effects of liraglutide in a real-world population of type 2 diabetic outpatients. Acta Diabetol. 2013;50:943–9. 6. Evans M, McEwan P, O’Shea R, George L. A retrospective, case-note survey of type 2 diabetes patients prescribed incretin-based therapies in clinical practice. Diabetes Ther. 2013;4:27–40. 7. Mulligan CM, Harper R, Harding J, McIlwaine W, Petruckevitch A, McLaughlin DM. A retrospective audit of type 2 diabetes patients prescribed liraglutide in real-life clinical practice. Diabetes Ther. 2013;4:147–51. 8. Li Q, Chitnis A, Hammer M, Langer J. Real-world clinical and economic outcomes of liraglutide versus sitagliptin in patients with type 2 diabetes mellitus in the United States. Diabetes Ther. 2014;5:579–90. 9. Thayer S, Wei W, Buysman E, Brekke L, Crown W, Grabner M, et al. The INITIATOR Study: pilot data on real-world clinical and economic outcomes in US patients with type 2 diabetes initiating injectable. Therapy Adv Ther. 2013;30: 1128–40. 10. Dupuy O, Bordier L, Garcia C, Brinkane A, Lormeau B, Popelier M, et al. Predictive criteria for clinical response to liraglutide: results from a “real life” study. Med Malad Metab. 2014;1:56–60.
Albert Lecube a,∗ , Cyntia Gonzalez b , Cristóbal Morales c a
Endocrinology and Nutrition Department, Arnau de Vilanova University Hospital, IRB-Lleida, UdL, Lleida, Spain b Endocrinology and Nutrition Department, Gregorio Mara˜ nón University Hospital, Madrid, Spain c Hospital de Día de Diabetes, Unidad de Investigación Clínica, Virgen Macarena University Hospital, UGC Provincial Endocrinologia y Nutrición, Sevilla, Spain ∗ Corresponding author. E-mail address: [email protected] (A. Lecube).
Eleven of the 135 patients with MEN 2A syndrome, reported HPT (8%). One case was excluded due to lack of follow-up (n = 10). The variables mentioned above are observed in Table 1. The average age of HPT diagnosis was 40 ± 16 years. All had the mutation at codon 634 (exon 11). The diagnosis was synchronous with medullary thyroid carcinoma (MTC) in 80% (5 surgical and 3 biochemical). Only one patient had associated symptomatology, reporting bone pain. The surgical technique used was: subtotal parathyroidectomy (60%), resection of one or two glands (30%) and total parathyroidectomy with autotransplantation (10%). Mean follow-up was 17 years (20 years in patients with subtotal/total parathyroidectomy vs 9 years in cases with smaller resection). 30% reported persistent hypoparathyroidism (29 vs 33%), and there were no cases of recurrent injury. There were 2 relapses, both in patients with subtotal parathyroidectomy (after 12 and 26 years), and both of them with C634R mutation. When comparing recurrence and complications with surgical technique, no differences (p > 0.05) were reported. When comparing recurrence with type of mutation, a closer relationship with C634R mutation was observed, although without significant differences (p = 0.067). The prevalence of HPT in MEN 2A syndrome of our series is lower than that reported in the literature (10–30%),7 and predominates in males, unlike most series.4 The age of emergence is similar,2,4,5 as well as the lack of associated symptomatology. Diagnosis was mainly synchronous with MTC, as usual,2–4,7 highlighting the surgical diagnosis. Parathyroidectomy was suggested in patients with macroscopically affected glands, as in our cases. Regarding postoperative complications, no case of persistent dysphonia has been reported. Previous studies even show a 6%
Scientific letters / Med Clin (Barc). 2016;146(9):414–417
417
Table 1 Epidemiological and clinical variables, surgical technique, and clinical course of patients with HPT in MEN 2A syndrome. No.
1 2 3 4 5 6 7 8 9 10
Epidemiological variables
Clinical variables
Age (years)
Sex
Mutation
Dx
31 14 52 47 71 45 41 44 18 36
M W M M M M M W W M
Tyr Arg Tyr Tyr Tyr Tyr Arg Arg Tyr Tyr
Fol Intra Pre Pre Pre Intra Fol Intra Intra Intra
Surgery technique
Analysis (Ca mg/dl/PTH ng/dl) 12 9 9.5 11 11 10 12 10 9.8 9.9
69 62 92 85 150 63 231 63 61 60
Clinical course
Px Qx
Tx Qx
Hypo PTH
Rx
Fol (years)
1 gland 2 gland 2 gland higher Sub Sub Sub Sub Sub Sub Total + autotx
TT + CLA TT TT + CLA TT + CLA TT + CLA TT TT TT + CLA TT + CLA TT + CLA
No No Yes Yes No Yes No No No No
No No No No No No Yes Yes No No
10 11 7 16 8 33 31 32 17 6
Arg, arginine mutation (C634R); autotx, autotransplantation; Dx, diagnosis; Gland, gland; HipoPTH, hypoparathyroidism; intra, intraoperative when performing thyroid surgery; W, woman; No., number of patient; pre, preoperative regarding thyroid surgery; Px Qx, parathyroid surgery; Tx Qx, thyroid surgery; Rx, recurrence; Fol, in follow-up after thyroid surgery (one year after surgery in n 1, 6 years after surgery in n 7); sub, subtotal; higher, higher; TT, total thyroidectomy; M, male; CLA, central lymphadenectomy; Tyr, tyrosine mutation (C634RY).
rate, being resection selective in some cases.5 The rate of persistent hypoparathyroidism ranges from 13 to 31%.2–5,8 Our series reaches 30%, but in 70% central lymphadenectomy had also been performed.8 In some papers the rate rises up to 50% when subtotal parathyroidectomy has been performed.2 In this study, no higher rate of hypoparathyroidism has been reported in these cases. Regarding recurrence, it has been observed that one case showed higher levels of serum calcium and PTH compared with the remaining, and the other showed a glandular weight >500 mg, both suggesting a more severe HPT. In 2011, Scholten et al.5 supported a smaller glandular resection, given the low rate of recurrence. However, patients with follow-up over 6 years did show recurrence. The same applies to the series of Kraimps et al.2 and O’Riordain et al.,3 where patients were monitored for 8 and 5.8 years, respectively. In our series, recurrence was after 12 and 26 years, and it might have been higher with lower resection. Therefore, when analyzing the recurrence of HPT, it is important to consider the follow-up time duration. Regarding genetics, higher HPT penetrance in codon 634 mutation (exon 11) is accepted.9,10 However, there is controversy over C634R mutation conferring increased risk of developing parathyroid disease.6,7,9,10 Our data prove a higher penetrance in this mutation, and it might be related to higher aggressiveness6 and a higher tendency to relapse. In conclusion, HPT at MEN 2 is rare, and subtotal parathyroidectomy provides good results. C634R mutation might cause higher recurrence. Given the rarity of this disease, it would be interesting to conduct multicenter studies to unify criteria and optimize the treatment of these patients. References 1. Dotzenrath C, Cupisti K, Goretzki PE, Yang Q, Simon D, Ohmann C, et al. Long-term biochemical results after operative treatment of primary hyperparathyroidism associated with multiple endocrine neoplasia types I and IIa: is a more or less extended operation essential. Eur J Surg. 2001;167:173–8.
2. Kraimps JL, Denizot A, Carnaille B, Henry JF, Proye C, Bacourt F, et al. 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 J Surg. 1996;20:808–12. 3. O’Riordain DS, O’Brien T, Grant CS, Weaver A, Gharib H, van Heerden JA. Surgical management of primary hyperparathyroidism in multiple endocrine neoplasia types 1 and 2. Surgery. 1993;114:1031–7. 4. Brandi ML, Aurbach GD, Fitzpatrick LA. Parathyroid mitogenic activity in plasma from familial multiple endocrine neoplasia type I. N Engl J Med. 1986;314:1287–93. 5. Scholten A, Schreinemakers JM, Pieterman CR, Valk GD, Vriens MR, Borel Rinkes IH. Evolution of surgical treatment of primary hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Endocr Pract. 2011;17: 7–15. 6. Valdés N, Navarro E, Mesa J, Casterás A, Alcázar V, Lamas C, et al. RET Cys634Arg mutation confers a more aggressive multiple endocrine neoplasia type 2A phenotype than Cys634Tyr mutation. Eur J Endocrinol. 2015;172:301–7. 7. Brandi ML, Gagel RF, Angeli A, Bilezikian P, Beck-Peccoz P, Bordi C, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001;86:5658–71. 8. Twigt BA, Scholten A, Valk GD, Rinkes IH, Vriens MR. Differences between sporadic and MEN related primary hyperparathyroidism; clinical expression, preoperative workup, operative strategy and follow-up. Orphanet J Rare Dis. 2013;8:50. 9. Mulligan LM, Eng C, Healey CS, Clayton D, Kwok JB, Gardner E, et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet. 1994;6:70–4. ˜ 10. Punales MK, Graf H, Gross JL, Maia AL. RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab. 2003;88:2644–9.
Beatriz Febrero a,b,∗ , José M. Rodríguez a,b , Antonio Ríos a,b , Pascual Parrilla a,b a
Unidad de Cirugía Endocrina, Servicio de Cirugía General, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain b Instituto Murciano de Investigación Biomédica, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain ∗ Corresponding author. E-mail address: [email protected] (B. Febrero).
Scientific letters / Med Clin (Barc). 2016;146(9):414–417
In conclusion, previous studies on the effectiveness of liraglutide conducted in real life-scenarios in Europe and the USA have shown liraglutide to be superior to exenatide, sitagliptin, and insulin glargine with respect to reductions in HbA1c and weight loss. In addition, some of the predictors of a better response seem to be younger age, shorter duration of T2D, and higher weight at baseline. Based on a population of patients followed for more than 2 years, we extend the list of predictors by adding female gender, insulin naïve, and absence of the need for insulin during follow-up. Financial and competint interest disclosure This work was supported by Novo Nordisk. The authors have no other relevant affiliations, financial involvement or financial conflict with the subject matter discussed in the manuscrit. The authors take full responsibility for this paper but are grateful to Manuela Rubio for providing writing assistance in the preparation of this manuscript. References 1. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38:140–9. 2. Barnett AH. The role of GLP-1 mimetics and basal insulin analogues in type 2 diabetes mellitus: guidance from studies of liraglutide. Diabetes Obes Metab. 2012;14:304–14. 3. Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009;32:84–90.
Hyperparathyroidism in multiple endocrine neoplasia type 2A syndrome. Surgical and genetic implications夽 Hiperparatiroidismo en el síndrome de neoplasia endocrina múltiple tipo 2A. Implicaciones terapéuticas y genéticas Dear Editor, Managing hyperparathyroidism (HPT) in multiple endocrine neoplasia (MEN) 2A syndrome is controversial. It is a rare disease and few studies are available, most of them old, multicentre, and with a limited number of patients. The treatment of choice has traditionally been the subtotal or total parathyroidectomy.1 However, multiglandular involvement is not synchronous. Therefore, some authors suggest a less aggressive treatment.2–5 On the other hand, recent studies have shown that some mutations may have a more aggressive symptomatology,6 so treatment might also have a genetic involvement. A retrospective analysis has been conducted with 135 patients with MEN 2A syndrome in a tertiary hospital, including those operated of HPT, excluding patients without follow-up. Clinical and epidemiological variables, treatment, postoperative complications and persistent or recurrent HPT have been analyzed. Statistics: descriptive, 2 test when possible and Fisher exact test in other cases. 夽 Please cite this article as: Febrero B, Rodríguez JM, Ríos A, Parrilla P. Hiperparatiroidismo en el síndrome de neoplasia endocrina múltiple tipo 2A. Implicaciones terapéuticas y genéticas. Med Clin (Barc). 2016;146:416–417.
4. Nyeland ME, Ploug UJ, Richards A, Carcia Alvarez L, Demuth D, Muthutantri A, et al. Evaluation of the effectiveness of liraglutide and sitagliptin in type 2 diabetes: a retrospective study in UK primary care. Int J Clin Pract. 2015;69: 281–9. 5. Fadini GP, Simioni N, Frison V, Dal Pos M, Bettio M, Rocchini P, et al. Independent glucose and weight-reducing effects of liraglutide in a real-world population of type 2 diabetic outpatients. Acta Diabetol. 2013;50:943–9. 6. Evans M, McEwan P, O’Shea R, George L. A retrospective, case-note survey of type 2 diabetes patients prescribed incretin-based therapies in clinical practice. Diabetes Ther. 2013;4:27–40. 7. Mulligan CM, Harper R, Harding J, McIlwaine W, Petruckevitch A, McLaughlin DM. A retrospective audit of type 2 diabetes patients prescribed liraglutide in real-life clinical practice. Diabetes Ther. 2013;4:147–51. 8. Li Q, Chitnis A, Hammer M, Langer J. Real-world clinical and economic outcomes of liraglutide versus sitagliptin in patients with type 2 diabetes mellitus in the United States. Diabetes Ther. 2014;5:579–90. 9. Thayer S, Wei W, Buysman E, Brekke L, Crown W, Grabner M, et al. The INITIATOR Study: pilot data on real-world clinical and economic outcomes in US patients with type 2 diabetes initiating injectable. Therapy Adv Ther. 2013;30: 1128–40. 10. Dupuy O, Bordier L, Garcia C, Brinkane A, Lormeau B, Popelier M, et al. Predictive criteria for clinical response to liraglutide: results from a “real life” study. Med Malad Metab. 2014;1:56–60.
Albert Lecube a,∗ , Cyntia Gonzalez b , Cristóbal Morales c a
Endocrinology and Nutrition Department, Arnau de Vilanova University Hospital, IRB-Lleida, UdL, Lleida, Spain b Endocrinology and Nutrition Department, Gregorio Mara˜ nón University Hospital, Madrid, Spain c Hospital de Día de Diabetes, Unidad de Investigación Clínica, Virgen Macarena University Hospital, UGC Provincial Endocrinologia y Nutrición, Sevilla, Spain ∗ Corresponding author. E-mail address: [email protected] (A. Lecube).
Eleven of the 135 patients with MEN 2A syndrome, reported HPT (8%). One case was excluded due to lack of follow-up (n = 10). The variables mentioned above are observed in Table 1. The average age of HPT diagnosis was 40 ± 16 years. All had the mutation at codon 634 (exon 11). The diagnosis was synchronous with medullary thyroid carcinoma (MTC) in 80% (5 surgical and 3 biochemical). Only one patient had associated symptomatology, reporting bone pain. The surgical technique used was: subtotal parathyroidectomy (60%), resection of one or two glands (30%) and total parathyroidectomy with autotransplantation (10%). Mean follow-up was 17 years (20 years in patients with subtotal/total parathyroidectomy vs 9 years in cases with smaller resection). 30% reported persistent hypoparathyroidism (29 vs 33%), and there were no cases of recurrent injury. There were 2 relapses, both in patients with subtotal parathyroidectomy (after 12 and 26 years), and both of them with C634R mutation. When comparing recurrence and complications with surgical technique, no differences (p > 0.05) were reported. When comparing recurrence with type of mutation, a closer relationship with C634R mutation was observed, although without significant differences (p = 0.067). The prevalence of HPT in MEN 2A syndrome of our series is lower than that reported in the literature (10–30%),7 and predominates in males, unlike most series.4 The age of emergence is similar,2,4,5 as well as the lack of associated symptomatology. Diagnosis was mainly synchronous with MTC, as usual,2–4,7 highlighting the surgical diagnosis. Parathyroidectomy was suggested in patients with macroscopically affected glands, as in our cases. Regarding postoperative complications, no case of persistent dysphonia has been reported. Previous studies even show a 6%
Scientific letters / Med Clin (Barc). 2016;146(9):414–417
417
Table 1 Epidemiological and clinical variables, surgical technique, and clinical course of patients with HPT in MEN 2A syndrome. No.
1 2 3 4 5 6 7 8 9 10
Epidemiological variables
Clinical variables
Age (years)
Sex
Mutation
Dx
31 14 52 47 71 45 41 44 18 36
M W M M M M M W W M
Tyr Arg Tyr Tyr Tyr Tyr Arg Arg Tyr Tyr
Fol Intra Pre Pre Pre Intra Fol Intra Intra Intra
Surgery technique
Analysis (Ca mg/dl/PTH ng/dl) 12 9 9.5 11 11 10 12 10 9.8 9.9
69 62 92 85 150 63 231 63 61 60
Clinical course
Px Qx
Tx Qx
Hypo PTH
Rx
Fol (years)
1 gland 2 gland 2 gland higher Sub Sub Sub Sub Sub Sub Total + autotx
TT + CLA TT TT + CLA TT + CLA TT + CLA TT TT TT + CLA TT + CLA TT + CLA
No No Yes Yes No Yes No No No No
No No No No No No Yes Yes No No
10 11 7 16 8 33 31 32 17 6
Arg, arginine mutation (C634R); autotx, autotransplantation; Dx, diagnosis; Gland, gland; HipoPTH, hypoparathyroidism; intra, intraoperative when performing thyroid surgery; W, woman; No., number of patient; pre, preoperative regarding thyroid surgery; Px Qx, parathyroid surgery; Tx Qx, thyroid surgery; Rx, recurrence; Fol, in follow-up after thyroid surgery (one year after surgery in n 1, 6 years after surgery in n 7); sub, subtotal; higher, higher; TT, total thyroidectomy; M, male; CLA, central lymphadenectomy; Tyr, tyrosine mutation (C634RY).
rate, being resection selective in some cases.5 The rate of persistent hypoparathyroidism ranges from 13 to 31%.2–5,8 Our series reaches 30%, but in 70% central lymphadenectomy had also been performed.8 In some papers the rate rises up to 50% when subtotal parathyroidectomy has been performed.2 In this study, no higher rate of hypoparathyroidism has been reported in these cases. Regarding recurrence, it has been observed that one case showed higher levels of serum calcium and PTH compared with the remaining, and the other showed a glandular weight >500 mg, both suggesting a more severe HPT. In 2011, Scholten et al.5 supported a smaller glandular resection, given the low rate of recurrence. However, patients with follow-up over 6 years did show recurrence. The same applies to the series of Kraimps et al.2 and O’Riordain et al.,3 where patients were monitored for 8 and 5.8 years, respectively. In our series, recurrence was after 12 and 26 years, and it might have been higher with lower resection. Therefore, when analyzing the recurrence of HPT, it is important to consider the follow-up time duration. Regarding genetics, higher HPT penetrance in codon 634 mutation (exon 11) is accepted.9,10 However, there is controversy over C634R mutation conferring increased risk of developing parathyroid disease.6,7,9,10 Our data prove a higher penetrance in this mutation, and it might be related to higher aggressiveness6 and a higher tendency to relapse. In conclusion, HPT at MEN 2 is rare, and subtotal parathyroidectomy provides good results. C634R mutation might cause higher recurrence. Given the rarity of this disease, it would be interesting to conduct multicenter studies to unify criteria and optimize the treatment of these patients. References 1. Dotzenrath C, Cupisti K, Goretzki PE, Yang Q, Simon D, Ohmann C, et al. Long-term biochemical results after operative treatment of primary hyperparathyroidism associated with multiple endocrine neoplasia types I and IIa: is a more or less extended operation essential. Eur J Surg. 2001;167:173–8.
2. Kraimps JL, Denizot A, Carnaille B, Henry JF, Proye C, Bacourt F, et al. 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 J Surg. 1996;20:808–12. 3. O’Riordain DS, O’Brien T, Grant CS, Weaver A, Gharib H, van Heerden JA. Surgical management of primary hyperparathyroidism in multiple endocrine neoplasia types 1 and 2. Surgery. 1993;114:1031–7. 4. Brandi ML, Aurbach GD, Fitzpatrick LA. Parathyroid mitogenic activity in plasma from familial multiple endocrine neoplasia type I. N Engl J Med. 1986;314:1287–93. 5. Scholten A, Schreinemakers JM, Pieterman CR, Valk GD, Vriens MR, Borel Rinkes IH. Evolution of surgical treatment of primary hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Endocr Pract. 2011;17: 7–15. 6. Valdés N, Navarro E, Mesa J, Casterás A, Alcázar V, Lamas C, et al. RET Cys634Arg mutation confers a more aggressive multiple endocrine neoplasia type 2A phenotype than Cys634Tyr mutation. Eur J Endocrinol. 2015;172:301–7. 7. Brandi ML, Gagel RF, Angeli A, Bilezikian P, Beck-Peccoz P, Bordi C, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001;86:5658–71. 8. Twigt BA, Scholten A, Valk GD, Rinkes IH, Vriens MR. Differences between sporadic and MEN related primary hyperparathyroidism; clinical expression, preoperative workup, operative strategy and follow-up. Orphanet J Rare Dis. 2013;8:50. 9. Mulligan LM, Eng C, Healey CS, Clayton D, Kwok JB, Gardner E, et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet. 1994;6:70–4. ˜ 10. Punales MK, Graf H, Gross JL, Maia AL. RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab. 2003;88:2644–9.
Beatriz Febrero a,b,∗ , José M. Rodríguez a,b , Antonio Ríos a,b , Pascual Parrilla a,b a
Unidad de Cirugía Endocrina, Servicio de Cirugía General, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain b Instituto Murciano de Investigación Biomédica, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain ∗ Corresponding author. E-mail address: [email protected] (B. Febrero).