Objective: To improve the knowledge of MEN1 natural history before 21 years old.

Transcription

1 ORIGINAL ARTICLE MEN1 Disease Occurring Before 21 Years Old: A 160-Patient Cohort Study From the Groupe d étude des Tumeurs Endocrines P. Goudet, A. Dalac, M. Le Bras, C. Cardot-Bauters, P. Niccoli, N. Lévy-Bohbot, H. du Boullay, X. Bertagna, P. Ruszniewski, F. Borson-Chazot, B. Vergès, J. L. Sadoul, F. Ménégaux, A. Tabarin, J. M. Kühn, P. d Anella, O. Chabre, S. Christin-Maitre, G. Cadiot, C. Binquet, and B. Delemer* Context: Multiple endocrine neoplasia Type-1 (MEN1) in young patients is only described by case reports. Objective: To improve the knowledge of MEN1 natural history before 21 years old. Methods: Obtain a description of the first symptoms occurring before 21 years old (clinical symptoms, biological or imaging abnormalities), surgical outcomes related to MEN1 Neuro Endocrine Tumors (NETs) occurring in a group of 160 patients extracted from the Groupe d étude des Tumeurs Endocrines MEN1 cohort. Results: The first symptoms were related to hyperparathyroidism in 122 cases (75%), pituitary adenoma in 55 cases (34%), nonsecreting pancreatic tumor (NSPT) in 14 cases (9%), insulinoma in 20 cases (12%), gastrinoma in three cases (2%), malignant adrenal tumors in 2 cases (1%), and malignant thymic-net in one case (1%). Hyperparathyrodism was the first lesion in 90 cases (56%). The first symptoms occurred before 10 years old in 22 cases (14%) and before 5 years old in five cases (3%). Surgery was performed before age 21 in 66 patients (41%) with a total of 74 operations: pituitary adenoma (n 9, 16%), hyperparathyroidism (n 38, 31%), gastrinoma (n 1, 33%), NSPT (n 5, 36%), and all cases of insulinoma, adrenal tumors, and thymic-net. One patient died before age 21 due to a thymic-net. Overall, lesions were malignant in four cases. Conclusions: Various MEN1 lesions occurred frequently before 21 years old, but mainly after 10 years of age. Rare, aggressive tumors may develop at any age. Hyperparathyroidism was the most frequently encountered lesion but was not always the first biological or clinical abnormality to appear during the course of MEN1. (J Clin Endocrinol Metab 100: , 2015) Multiple endocrine neoplasia type 1 (MEN1) is an inherited disease that predisposes carriers to primary hyperparathyroidism (phpt), endocrine enteropancreatic tumors, pituitary adenomas, adrenal, and thymic/bronchial neuroendocrine tumors (th-net/br-net). MEN1 disease may display various clinical associations, and the criteria for diagnosis were established first in Gubbio (Italy) and then regularly updated (1 4). MEN1 disease is usually described as an autosomal dominant cancer syndrome with a very progressive but finally high penetrance during the lifespan (2, 5, 6). The MEN1 gene located on chromosome 11q13 is considered as tumor suppressor, given the loss of heterozygoty (LOH) in MEN1- related tumors DNA (7, 8). MEN1 gene encodes menin, a 610 amino acid protein expressed in all tissues tested (9, 10). Menin interacts with a large number of intracellular molecules, including transcriptional factors, cytoskeletal components, and proteins involved in the control of DNA replication (9 12). Because of its low and progressive penetrance, MEN1 disease has been poorly studied during ISSN Print X ISSN Online Printed in U.S.A. Copyright 2015 by the Endocrine Society Received September 26, Accepted January 9, First Published Online January 16, 2015 * Author Affiliations are shown at the bottom of the next page. Abbreviations: EUS, endoscopic ultrasound; GTE, Groupe d étude des Tumeurs Endocrines; hgh, growth hormone; LOH, loss of heterozygoty; MEN1, multiple endocrine neoplasia type 1; MRI, magnetic resonance imaging; NIH, National Institutes of Health; NSPT, nonsecreting-pancreatic-tumors; phpt, primary hyperparathyroidism; ZES, Zollinger-Ellison Syndrome jcem.endojournals.org J Clin Endocrinol Metab, April 2015, 100(4): doi: /jc

2 doi: /jc jcem.endojournals.org 1569 childhood and adolescence. Only case reports are available (1, 13 22). This lack of data prompted us to carry out a new study focused on young MEN1 patients belonging to the GTE cohort (Groupe d étude des Tumeurs Endocrines) and presenting any clinical symptoms, and/or biological and/or imaging changes before the age of 21. The aims of this study were to describe the natural history of MEN1 patients, the first symptoms occurring before the age of 21, the surgical procedures performed, and consequently to produce evidence-based data in order to improve recommendations for detection and follow-up. Population, data collection, and method Population One hundred and sixty patients (96 girls and 64 boys) presenting at least one MEN1-related clinical symptoms, and/or biological changes and/or imaging abnormalities before 21 years were studied. MEN1 mutation tests were performed in 157 of the 160 patients (98%) and found positive in 155 (99%). The 2 negative patients belonged to MEN1 families. They progressively presented with the Zollinger- Ellison Syndrome (ZES), phpt, and pituitary adenoma for one and ZES associated with pituitary adenoma for the other. Mutations were classified as truncating (60 frameshift, 22 nonsense), nontruncating mutations (20 missense, 5 in-frame deletions or insertions), or as others in 48 cases (splicing and intronic mutations, intragenic and genic rearrangements). One hundred and six patients (66%) were familial cases followed up during their childhood using international recommendations (1). Nineteen patients (12%) were familial cases who were followed up later and/or less frequently, and 37 patients (23%) were index cases (isolated cases or first cases from a new family) who were followed up after the diagnosis of the first symptomatic lesion. Overall, MEN1 lesions were detected in 125/ 172 (73%) patients who followed a screening program under the age of 21. Data collection This series of 160 young patients was part of the 924- patient MEN1-GTE cohort, and was extracted from the database on March 29, 2010 (17%). The 764 remaining not studied patients were MEN1 patients whose first symptoms occurred after 20 years old. Initial clinical data were provided by the referent physician. A copy from each patient s file was obtained, anonymized, and stored at the University of Burgundy. A Case Report Form was created, filled in, and regularly updated from copies of the patients medical files, and regular visit by the surgeon in charge of the database (PG). This cohort was approved by the CCTIRS (Consultative Committee on Treatment of Information in Health Research, file number ) and the CNIL (National Committee for data protection, authorization number DR ). Informed consent was not required, but patients had the right to withdraw their data from the cohort. Materials and Methods The clinical symptoms and/or biological abnormalities and/or lesions detected by imaging before 21 years of age and related to MEN1 disease were described. Each type of lesion was recorded with complementary data: date of diagnosis, age at diagnosis, imaging results, indication for surgery, type of operation, surgical outcome, size of the tumors, pathological reports obtained from surgery or from endoscopy with biopsy and reported using the ongoing classification, follow-up, and survival status. The first manifestations of MEN1 disease were considered simultaneous when they occurred during the same month. Criteria for insulinoma diagnosis were based on the presence of hypoglycemic symptoms associated with low plasma glucose concentrations ( 0.45 g/l) and inappropriately high serum insulin ( 3 mui/l) or C-peptide ( 0.6 ng/ml). Four criteria were required to include patients with ZES related symptoms: (1) The presence of continuous specific clinical symptoms associated with endoscopic features of ZES. (2) At least 2 out of 4 National Institutes of Health (NIH) criteria at the time of diagnosis (23). (3) The impossibility to withdraw high-dose Proton Pomp Inhibitors. (4) A duration of symptoms inferior to 6 years. At the time of the study, 67% of the patients had reached the age of 21, 90% the age of 15, 97% the age of 10, and 100% the age of 5. Hardy s classification was used to categorize pituitary adenomas (24). Statistical analysis Results for qualitative variables were expressed as percentages. Pearson s chi-2 test or Fischer s exact test was used when appro- Centre Hospitalier Universitaire de Dijon (P.G.), Endocrine Surgery, Dijon, France; INSERM U866, Dijon, France; University of Burgundy, Dijon, France; Service d Endocrinologie et Maladies Métaboliques (A.D., N.L-B.), Centre Hospitalier Universitaire, Hôpital Robert Debré, Reims, France, Clinique d Endocrinologie (M.L.), Centre Hospitalier Universitaire, Nantes, France; Service de Médecine Interne et Endocrinologie (C.C-B.), Clinique Marc Linquette, Centre Hospitalier Régional et Universitaire, Lille, France; Service d Oncologie Médicale (P.N.), Institut Paoli- Calmettes, APHM, Université Aix-Marseille, Marseille, France; Service d Endocrinologie (H.dB.), Centre Hospitalier de Chambéry, Chambéry, France; Département d Endocrinologie (X.B.), Hôpital Cochin, Université Paris Descartes, Paris, France; Service de Gastroentérologie-Pancréatologie (P.R.), APHP, Hôpital Beaujon et Université Paris 7 Denis Diderot, Clichy, France; Fédération d Endocrinologie (F.B-C.), Hospice Civils de Lyon et Université Lyon 1, Groupement Hospitalier Est. Lyon, France; Service d Endocrinologie (B.V.), Diabète et Maladies Métaboliques, Centre Hospitalier Universitaire de Dijon, Hôpital du Bocage, Dijon, France; Département d Endocrinologie (J.L.S.), Hopital de l Archet, Nice, France; Service de Chirurgie Générale (F.M.), Viscérale et Endocrinienne, Groupement Hospitalier Universitaire Est, Hôpital de la Pitié, Paris, France; Service d Endocrinologie (A.T.), Centre Hospitalier Universitaire, Hôpital du Haut Levêque, Pessac, France; Département d Endocrinologie (J.M.K.), Hôpital Universitaire de Rouen. Rouen, France; Service d Endocrinologie (P.dA.), Centre Hospitalier d Avignon, Avignon, France; Service d Endocrinologie (O.C.), Diabète et Maladies Métaboliques, Centre Hospitalier Universitaire de Grenoble, Hôpital Michalon, Grenoble, France; Service d Endocrinologie (S.C-M.), Centre Hôpitalier Universitaire. Hôpital St-Antoine, Paris, France; Service d Hépato-Gastro-Entérologie et de Cancérologie Digestive (G.C.), Centre Hospitalier Universitaire, Hôpital Robert Debré, Reims, France; INSERM (C.B.), CIC1432, Dijon, France; Centre Hospitalier Universitaire de Dijon (B.D.), CIC, Module Épidémiologie Clinique/Essais Cliniques, Dijon, France; INSERM U866, Dijon, France

3 1570 Goudet et al MEN1 Disease Before 21 Years Old J Clin Endocrinol Metab, April 2015, 100(4): Table 1. Characteristics of the Population priate. Continuous variables were expressed as means followed by their standard deviation [m(sd)]. A p-value below 0.05 was considered significant. Stata software version 9.0 (Stata Corp.) was used. Results N Women N (%) Index Cases a N (%) Patients Screened for MEN1 (DNA Testing) N (%) phpt was found in 122 patients (75%), and most of the time with only biological abnormalities (83%). A pituitary adenoma was present in 55 patients (34%). Clinical symptoms were found in 55% of them. Pancreatic NETs [n 37 (23%)] ranked third in frequency. Nonsecreting-pancreatic-tumors (NSPT) (n 14 [9%]) were exclusively revealed by imaging. Insulinoma (n 20 [12%]), gastrinoma (n 3 [2%)], adrenal tumors (n 2 [1%]), and Mean Age at First Symptoms Years [SD] Mean Age at Diagnosis Years [SD] Mean Delay of Diagnosis Years [SD] Diagnosis After 20 yr old N phpt b (57%) 19 (16%) 88 (72%) 15 [3] 16 [4] 1 [4] 2 0 Pituitary adenoma (76%) 11 (20%) 38 (69%) 16 [3] 17 [4] 1 [4] 2 0 Insulinoma (60%) 13 (65%) 3 (15%) 14 [4] 15 [4] 2 [3] 1 0 NSPT 14 8 (57%) 0 (0%) 13 (93%) 16 [2] 16 [2] Zollinger-Ellison 3 2 (67%) 2 (67%) 1 (33%) 13 [6] 16 [8] 2 [2] 1 0 Syndrome Adrenal NET 2 1 (50%) 1 (50%) 0 (0%) 10 [9] 10 [10] 0 [0] 0 0 Thymic NET 1 0 (0%) 1 (100%) 1 (100%) Death Before the Age of 21 N Abbreviations: NSPT, non-secreting pancreatic tumor; NET, neuro endocrine tumor. No bronchial NET was disclosed. a Index cases are MEN1 patients with no known family background at the time of diagnosis. These patients are either isolated cases or are the first cases of a new family. b Primary hyperparathyroidism. Table 2. Lesions, Clinical Symptoms, and Operation Rates Depending on Age Categories of Age Clinical Features phpt th-net (n 1 [1%]) were all clinically symptomatic. The details of these data are classified by five-year periods and are shown in Tables 1 and 2. The youngest patients affected by each type of lesion are described in Table 3. Sixty-six patients (41%) were operated on before 21 years of age with a total of 74 operations. Ninety percent of insulinomas, all adrenal tumors and th-nets were operated on contrasting with pituitary adenomas (n 9, 16%), phpt (n 38, 31%), gastrinomas (n 1, 33%), and NSPT (n 5, 36%). Seven patients were operated on before 11 years old (4%). Four patients had malignant tumors (one gastrinoma with liver metastases, two 7-cm adrenal carcinomas, and one multimetastatic thymic carcinoma operated on at 7, 3, 16, and 15 years old, respectively). One patient died before 21 Pituitary Adenoma Insulinoma Gastrinoma NSPT Adrenal Tumors Thymic NET 1 to 5 years Clinical symptoms 0 (0%) 1 (100%) 1 (100%) Operated cases a Total to 10 years Clinical symptoms 2 (22%) 0 (0%) 4 (100%) 1 (100%) Operated cases a Total to 15 years Clinical symptoms 3 (8%) 9 (36%) 7 (100%) 0 (0%) Operated cases a Total to 20 years Clinical symptoms 16 (22%) 24 (86%) 8 (100%) 2 (100%) 0 (0%) 1 (100%) 1 (100%) Operated cases a Total Total Clinical symptoms 21 (17%) 30 (55%) 20 (100%) 3 (100%) 0 (0%) 2 (100%) 1 (100%) Operated cases years old Total Abbreviation: NET, neuro endocrine tumor. a Number of operated cases during the five-year period.

4 doi: /jc jcem.endojournals.org 1571 Table 3. The Youngest MEN1 Cases by Lesion Age at First Symptoms (years) Gender Related Lesion Means of Detection Detailed Case-Reports Treatment Case No. 1 3 Male Adrenal Clinical symptoms Virilization A 7-cm adrenal carcinoma was removed at 3 years old cobaltotherapy (5 Gy) chemotherapy (5-fluorouracile vinblastine sulfate). Still alive at 39 years old Case No. 2 4 Male Biological phpt Biological Calcemia 2.65 mmol/l [ ] Still not operated on at 9 years old abnormalities Ionized calcemia 1.75 mmol/l [ ] PTH 27.5 pg/ml [19 75] Case No. 3 5 Female Insulinoma Clinical symptoms Confusion Left pancreatectomy for a 13 mm begnin insulinoma. Symptom free at 10 years old Case No. 4 6 Female Zollinger-Ellison syndrome Clinical symptoms Diarrhea, grade II esophagitis, Multiple ulcers (duodenum antrum) at 7 years old Gastrinemia 3000 pg/ml without PPI Positive secretin test on gastrin Operated on at 7 years old. Four centimeter retropancreatic metastatic node. Two millimeter prepyloric gastrinoma. Positive immunostaining (100% for gastrin and chromogranin A). Reoperated on at 14, 18, and 19 years old for local recurrence, liver metastasis treated by metastasectomy and radio-frequency ablation Case No. 5 8 Female Symptomatic phpt Clinical symptoms Right nephrolithiasis Hypercalciuria Positive cervical ultrasound showing a right PIII enlargement Operated on at 8 years old. 1 cm right PIII adenoma removed Calcemia 2.42 mmol/l [ ] and no hypercalciuria at 14 years old Case No Female Hardy 1 pituitary adenoma MRI MRI: 10 mm pituitary adenoma with cystic component No treatment. Stable at 20 years old Abbreviations: NET, neuroendocrine tumor; PPI, proton pump inhibitor. years old because of the rapid metastatic spread of a thymic tumor. Hyperparathyroidism Most of the 122 phpt cases occurred after 10 years [110/122 (90%)]. Twenty-one cases (17%) presented clinical symptoms [18 (86%) urolithiasis, 7 (33%) fatigue, 2 (1%) bone pain] with the earliest one at 8 years (urolithiasis) (Table 3, case 2). Before 6 years old, phpt was very rare (n 3) and asymptomatic, with elevation of ionized calcium and inappropriate PTH levels. By contrast, mean blood calcium levels were high in phpt patients diagnosed after 5 years old and were identical whatever the five-year period [2.7 (0.2) mmol/l]. phpt was the first manifestation of the disease in 90 cases ie, in 56% of MEN1 cases, and was discovered by biological screening in most of them [71/90 (79%)]. No patient was operated Table 4. Categories of Age on before 8 years old. The indication for surgery was either clinical symptoms (n 21) or calcemia above 2.75 mmol/l (n 17). The number of parathyroid glands removed was 3.5 glands [12 (32%)], 3 glands [7 (18%)], 2.5 glands [2 (5%)], 2 glands [6 (16%)], 1 gland [10 (26%)] (one missing data). The outcomes of surgery are shown in Table 4. Pituitary adenoma Pituitary adenoma (n 55) occurred mostly in females (76%), never before 10 years old, and were clinically symptomatic at the time of diagnosis in 30 cases (55%) mostly after 15 years [16/28 (57%) vs 8/27(30%), (P.04)]. Thirteen patients were first diagnosed by either MRI (24%) or hormonal screening (22%). Clinical symptoms were amenorrhea/galactorrhea [24 (44%)], cephalalgia [7 (13%)], visual impairment [5 (9%)], Cushing s disease [2 Hyperparathyroidism. Surgical Techniques and Results at the Last Follow-Up Before 21 Years Old Surgical Technique PTX Parathyroi-dectomy Number of Operated Patients N (%) Postoperative Calcemic Status N (%) Re Operation Rate Before 21 Years old Surgical Technique in Case of re Operation Calcemic Status at the Last-Follow-Up Before 21 yr old N (%) 6 to 10 years Subtotal PTX 0 (0%) Normo calcemia 1 (100%) Normo calcemia 1 (100%) Less than subtotal PTX 1 (100%) Hypo calcemia Hypo calcemia Hyper calcemia Hyper calcemia 11 to 15 years Subtotal PTX 1 (20%) Normo calcemia 2 (40%) 1 (20%) Successful resection of a right P3. Normo calcemia 3 (60%) Less than subtotal PTX 4 (80%) Hypo calcemia 1 (20%) Hypo calcemia 1 (20%) Hyper calcemia 2 (40%) 1 (3%) Left P3 previously removed Hyper calcemia 1 (20%) 16 to 20 years Subtotal PTX 11 (35%) Normo calcemia 21 (71%) Unsuccessful resection of right P3 and P4 Normo calcemia 21 (71%) Less than subtotal PTX 20 (65%) Hypo calcemia 3 (10%) Left P4 previously removed Hypo calcemia 3 (10%) Hyper calcemia 7 (29%) Hyper calcemia 7 (29%) Total n 37 a Subtotal PTX 12 (32%) Normo calcemia 24 (65%) Normo calcemia 25 (67%) Less than subtotal PTX 25 (68%) Hypo calcemia 4 (11%) Hypo calcemia 4 (11%) Hyper calcemia 9 (24%) 2 (5%) See above Hyper calcemia 8 (22%) Subtotal PTX: subtotal parathyroidectomy i.e. resection of three glands and a half. Less than subtotal PTX: less than subtotal parathyroidectomy i.e. resection of less than 3 and a half glands. P3 and P4: inferior and superior parathyroid glands. a One case is missing (incomplete surgical data).

5 1572 Goudet et al MEN1 Disease Before 21 Years Old J Clin Endocrinol Metab, April 2015, 100(4): (4%)], acromegaly [1 (2%)]. The youngest case was detected by imaging at 10 years old (Table 3, case 6). Pituitary adenoma revealed the disease in 34 cases ie, in 21% of MEN1 cases most of the time by hormonal or imaging screening [25/34 (73%)]. Overall the spectrum of secretions related to pituitary adenoma was broad: 38 (69%) prolactinomas, four of which co-secreted either growth hormone (hgh) (n 2) or Adreno Cortico Trophic Hormone (ACTH) (n 2), 14 (25%) nonsecreting adenomas, one hgh-secreting adenoma, one ACTHsecreting adenoma, and was unknown for one patient. Concerning the size of the adenoma, there were 27 (49%) Hardy 1, 15 (27%) Hardy 2, 7 (13%) Hardy 3, and 6 (11%) Hardy 4. The size of the adenoma depended on gender: 7/13 (54%) males were classified as Hardy 3 or 4 vs 6/42 (14%) females (P.01). Nine (16%) patients were operated on. A trans-sphenoidal approach was used in 6 patients and a transcranial approach in 3. Insulinoma Insulinoma (n 20) revealed the disease in 16 cases ie, in 10% of MEN1 cases. The first case occurred before 5 years old (Table 3, case 3) and the number of cases observed at each five-year period increased regularly. Two main symptoms related to hypoglycemia revealed insulinoma: loss of consciousness or coma [11 (55%)] and weakness [9 (45%)], associated with convulsions in three cases. Weakness occurred spontaneously (n 3), with exercise (n 2) or when fasting (n 4). All the patients were operated on (2 of them at 21 years old). Surgery was immediately successful in 17 cases (85%) but required a second operation in three cases (15%). The successful operations were left pancreatectomy [15 (75%)] removing at least the tail of the pancreas and possibly associated with enucleation(s) of the rest of the gland (n 3) and rarely enucleation(s) of the tail [2 (10%)]. Three other cases (10%) were operated on by single or multiple enucleation and were unsuccessful. Patients needed to undergo repeat surgery rapidly using left pancreatectomy to be cured. The mean size of the removed tumors was 15 6 mm, and 25% of them measured 20 mm or more. All of them were classified as benign tumors. Nonsecreting pancreatic tumor Among a total of 14 cases always revealed by imaging, NSPT was the first lesion discovered in only three cases (2%). Left pancreatectomy was performed in three cases, enucleation of three tumors in one case and partial resection of the head of pancreas in one case. The mean size of the largest NSPT was 18 mm, and 43% of them measured 20 mm or more. The most critical tumor was a 4-cm grade 2 NET associated with multiple associated NETs and resected by left pancreatectomy. The patient was 13 years old. One to 5 tumors per patient were found (mean 1.8) in the 9 nonoperated patients. The size of the largest tumors ranged from 3 to 26 mm (mean 11.4 mm). Zollinger-Ellison syndrome Symptoms of the ZES occurred before 21 years old in 3 cases, thus revealing MEN1 disease, ie, in 2% of all MEN1 cases. ZES cases are described in Table 5. The youngest case was 6 years old at the first symptoms (Table 3, case 4) (Table 5, case No. 553). Adrenal tumor The two cases of adrenal tumor were carcinomas. Both presented clinical and biological symptoms of hyperandrogenism. A 7-cm tumor was removed in a 16-year-old girl. The tumor was classified with a Weiss score of 6. Another 7-cm tumor was removed in a 4-year-old boy in The tumor was considered malignant because of the rapid evolution of the clinical symptoms and because of the results of the pathological report at the time: large size of the tumor, numerous nuclear abnormalities, intravascular emboli, and hemorrhagic areas. The patient was treated by chemotherapy and radiotherapy (Table 3, case 1). Both patients were still alive at 20 years old. Thymic and bronchial tumors One case of thymic NET (1%) occurred in a 16-year old boy who died 49 months later from local spread and multiple bone metastases of a poorly differentiated NET. This patient presented symptoms of chest pain and medullar compression. No case of br-net was evidenced. Discussion This large, multicenter MEN1study addresses the issue of MEN1 symptoms and surgical treatments occurring during the first two decades of life. Most of the lesions occurred after 10 years of age, but symptomatic phpt and insulinomas may occur sooner. Rare, aggressive lesions, such as adrenal carcinoma, thymic carcinoma, gastrinoma also need to be highlighted because they were life-threatening and occurred at any age. The fact that no more than 65% of the population followed a screening program from age 5 10 may appear as a drawback in this study. Indeed, index cases (23%) were followed up later in the absence of a family history of MEN1 and unfortunately there are also noncompliant families (12%) in real life. Nevertheless, this probable underestimation of lesion frequency during the first years of life does not cast doubt on the conclusions in terms of minimal rules for detection.

6 doi: /jc jcem.endojournals.org 1573 Table 5. Zollinger-Ellison Patients Identity Number in the GTE Registry Sex Female Male Female Family background Index case MEN1 family with another ZES case (father) MEN1 family with metastatic ZES cases Age at first symptoms Clinical data Growth faltering. Abdominal pain. Vomiting. Diarrhea. Esophagitis grade II. Narrowed pylorus. Two ulcers in the antrum. Diffuse erosive gastritis. Hyperplastic gastric folds. Helicobacter pylori. Symptoms resolved under PPI s and antibiotics. Recurred after treatment. Abdominal Slowly increasing symptoms: abdominal pain and intermittent vomiting episodes. Selftreatment using PPIs. An endoscopy performed after emergency surgery showed: Esophagitis Grade II and gastric stasis with multiple duodenal ulcers Slowly increasing symptoms requiring more PPI s: abdominal pain, heart burn, diarrhea (4 times a day). Endoscopy showed grade II esophagitis, multiple gastrointestinal ulcers and hyperplastic gastric folds ultrasound showed a retroduodenal tumor (node) Impossibility to withdraw Omeprazole 40 mg/d Omeprazole 40 mg/d Lanzoprazole 45 mg/d PPI Highest fasting serum 3000 pg/ml (N 125) 870 pg/ml (N 100) 610 pg/ml (N 125) gastrin without PPI or renal insufficiency BAO 15 meq/h in Yes Refused the test Not done unoperated patient Gastrin increase after Yes Refused the test Not done secretin injection Positive histological confirmation of gastrinoma Gastrin-positive prepyloric NET, large prepancreatic gastrinpositive metastatic node, NET liver metastases phpt was the most prevalent lesion, as it is the case in adults. Rare cases of early phpt (n 3) were detected before age 6 but were only related to mild biological abnormalities. First clinical symptoms occurred at 8 years old. Only one case required surgery before 10 years. Many case reports are in accordance with these results showing that the earliest symptoms appeared between 5 and 11 years old (1, 13, 15, 16). These results also emphasize the fact that phpt is not always the first biological or clinical abnormality to appear during the course of MEN1 disease since phpt occurred as the first symptom in only 56% of these young patients. Calcium measurement and MEN1 mutation tests in families at risk might be proposed in children as young as 5 years of age. As far as surgery was concerned, only 50% of the patients were operated on by subtotal parathyroidectomy (3.5 glands or 3 glands with a normal one left in situ) even though it is the recommended operation (4). Fortunately, 67% of them had their hypercalcemia controlled during the study period. These Gastrin-positive peripancreatic metastatic nodes removed during an emergency laparotomy for hemostatic splenectomy (car accident) Abbreviations: NET, neuroendocrine tumor; PPI, proton pump inhibitors; BAO, basal acid output. Two gastrin positive NETs previously enucleated from the head during left pancreatectomy for large associated NETs of the pancreatic tail. Duodenal submucosal gastrin-positive NETs obtained by endoscopy results are comparable to data from the literature regarding adult MEN1 patients when appropriate subtotal parathyroidectomy was performed (25 27). Persistent or recurrent hypercalcemia is found in 40 60% of adult patients within years (25 27). Therefore, the question of the timing of surgery and the right operation to treat phpt during the two first decades needs to be raised in young MEN1 patients. Pituitary adenoma was the second most frequent lesion in children. Like in adults, prolactinoma was predominant although all kinds of hypersecretion were represented (28). Pituitary adenoma occurred from age 10 (2 cases) and before any other MEN1 lesion in 21% of the cases. Several cases have already been described in the literature: an isolated case at 5 years old (19) and eleven cases between 12 and 17 years old (18, 20, 22, 29) some of them occurring as the first manifestation of NEM1. Small pituitary adenomas are visible on MRI and pituitary hormonal secretions can be modified before any clinical

7 1574 Goudet et al MEN1 Disease Before 21 Years Old J Clin Endocrinol Metab, April 2015, 100(4): symptoms appear. However, half of the patients presented with a macroadenoma with an overall high frequency of clinical symptoms (55%). The group of patients of more than 15 years old seemed to be more exposed to serious tumoral or hormonal symptoms. As already noted in MEN1 disease, there is a gender-related difference regarding pituitary adenomas (6) with a 3.2/1 female/male sex ratio. Nevertheless, macroadenomas were more frequent among males, indicating a more severe pituitary disease in boys. We thus concluded that looking for any pituitary adenoma by magnetic resonance imaging (MRI) and by measuring PRL and IGF-1 in boys and girls no later than age 10 is wise. Discussing indications for surgery, techniques and outcomes seems inappropriate since only nine patients were operated on and since prolactinomas usually respond to medical therapy. Insulinomas may occur very early in the course of the disease since the youngest case presented symptoms of glycopenia at 5 years old. Another case of insulinoma occurring at 7 years old has been reported (20). Later in life, the number of incidental symptoms increased regularly, confirming the relative importance of this lesion in childhood. Insulinomas were the first manifestation of MEN1 in 10% of the 160 cases. Most of these occurred in index cases (65%). Therefore, these insulinomas could have been life-threatening since patients presented neurological symptoms. Nevertheless, no patients died, and none of the removed tumors were malignant. All of the patients were operated on within 2 years. Left pancreatectomy associated or not with complementary enucleation(s) of the remaining gland was the most successful operation. None died and all were free of symptoms thereafter. We thus concluded that parents, young patients, and general practitioners need to be taught about the symptoms of hypoglycemia that may occur in MEN1 families even at an early age. Because of the potentially life-threatening complications of insulinoma, we recommend testing for fasting glucose annually from the age of 5 onwards. Measuring insulin seems to be unnecessary since insulin remains in normal ranges when hypoglycemia is absent (2, 5). NSPT was revealed by imaging. The youngest case was 13 years old. Recent international recommendations do propose pancreas screening programs on a yearly basis, using MRI, CT or endoscopic ultrasound (EUS) before the age of 10 (4). Present and already published data confirm that large pancreatic tumors may develop between 10 and 20 years old (17, 30, 31). Among the 14 cases reported in this paper, five patients required surgery before 21 years because the tumor was larger than 2 cm. The frequency of imaging work-ups is debatable since rate of tumor growth is unknown. Starting at 10 years old and performing one imaging examination every other year may already be a substantial improvement compared with previous recommendations that date back to As far as the choice of imaging is concerned, a recent GTE study suggested that both MRI and EUS investigations should be done during the initial work-up for MEN1 to minimize the risk of not seeing a tumor 10 mm (32). Therefore, we may recommend MRI every other year, starting at age 10 for the detection of NSPT, but the question of the age for the first EUS examination is still pending. Another recent study showed that other biological assays, such as chromogranin A, pancreatic polypeptide or glucagon do not seem useful (33). Indeed, indications for surgery mainly depend on tumor size and/or growth rate (34, 35). As far as adrenal tumors are concerned, it is very difficult to draw any precise conclusions since only two cases were found in this series. Underestimation of slight enlargement or small nodules of the adrenal glands is plausible for many reasons: The use of multidetector CT scan dates back to 1998, radiological screening begins only by the age of 10, and the use of EUS is rare during the two first decades of life. Indeed, one out of three adrenal lesions identified by EUS may be missed by CT among MEN1 patients (36). Nevertheless, it is important to show that both declared tumors were carcinomas, both patients presented clinical symptoms of virilization and both were cured during the study period. We therefore concluded that adrenal tumor may be detected using the same MRI as that proposed to detect NSPT every other year. No biochemical testing is recommended unless clinical symptoms/or tumor 1 cm on imaging (4, 37). ZES was a rare condition, and by contrast to adults, less frequent than insulinomas (5). Functional symptoms were always present. One case occurred before 10 years of age, illustrating the fact that rare and aggressive tumors may occur at any age in MEN1 patients. Another 12-year-old patient with ZES was reported in the NIH series (38). Some cases of ZES may have been missed because of the insidious course of gastro-intestinal symptoms, the unreliability of many gastrin radio immunoassays and the easy use of antiproton medical treatment (38 40). Except for one very exceptional case, patients were not operated on for gastrinoma before 21 years. Teaching parents, young patients, and general practitioners about the clinical symptoms of ZES in MEN1 families is important. Yearly testing for gastrin from age 10 onwards seems appropriate even though normal gastrin levels do not exclude the diagnosis. Performing esophago gastro duodenoscopy and the complete battery of biological tests for ZES makes sense as soon as any gastro-intestinal symptoms occur. The issue concerning th-net is not its frequency, which is very low (41), but its severity. Th-NET was the only cause of rapid death within one year of a 16-year-old

8 doi: /jc jcem.endojournals.org 1575 Table 6. Comparison of Consensus Statements Tumor Age to Begin (year) Biochemical Test (plasma or serum) Annually Consensus statements on MEN1 (Brandi ML, JCEM, 2001) Parathyroid 8 Calcium (especially Ca2 ), PTH None Pancreatic NET Gastrinoma 20 Gastrin, gastric acid output; secretinstimulated gastrin None Imaging Test (time interval) Insulinoma 5 Fasting glucose, insulin None Other pancreatic NET 20 Chromogranin-A; glucagon; proinsulin Anterior pituitary 5 PRL; IGF-1 MRI (every 3 years) Adrenal No recommendation Foregut carcinoid 20 None CAT Suggested statements on MEN1 (Thakker RV, JCEM, 2012) Parathyroid 8 Calcium, PTH None Pancreatic NET Gastrinoma 20 Gastrin ( gastric ph) None Insulinoma 5 Fasting glucose, insulin None 111 In-DTPA octreotide scan; CAR or MRI (every 3 years) Other pancreatic 10 Chromogranin-A; pancreatic polypeptide; MRI, CT or EUS (annually) NET glucagon; VIP Anterior pituitary 5 PRL; IGF-1 MRI (every 3 years) Adrenal 10 None, unless symptoms or signs of functioning tumor and/or tumor 1 cm are identified on imaging Thymic and bronchial carcinoid MRI or CT (annually with pancreatic imaging) 15 None CT or MRI (every 1 2 years) Recommendations under debate in the GTE group (not validated) Parathyroid 5 Calcium None Pancreatic NET Gastrinoma 10 a Gastrin None Insulinoma 5 a Fasting glucose None Other pancreatic NET (?) None MRI every 2 years EUS (?) Anterior pituitary 10 PRL; IGF-1 MRI every 2 years Adrenal 10 None, unless tumor 1 cm is identified on MRI every 2 years Thymic/bronchial NET imaging 15 None CT or MRI? Frequency? In men only? Families with clusters? a Parents should be taught about related clinical signs of the Zollinger Ellison-Syndrome and insulinoma as soon as the genetic testing is ascertained. boy in our series (42). This rapidly-growing type of tumor theoretically requires annual imaging of the chest (4). Nevertheless, it is impossible to propose a yearly CT scan because of the cumulative radiation which could be harmful in the large majority of MEN1 population. Therefore, this question remains unsolved since MRI is not recommended for thoracic evaluation. Potential br-net would also benefit from the same imaging, knowing than no case was evidenced here and that only one case at 20 years old has been described in the literature (43). No genotype-phenotype correlation was demonstrated in the GTE cohort or in the literature (44). Therefore, a new analysis in this subgroup of young patients did not seem statistically pertinent. Moreover, no cluster was evidenced among family members of patients with aggressive tumors. Therefore, the general rule is still that early genetic screening and a preclinical work-up are required in all patients. The 73% yield of lesion detection among screened patients under 21 favors this attitude. Recent data also confirm that early screening improves prognosis and survival in patients with complex hereditary neuroendocrine syndromes (45). This first comprehensive analysis of 160 young MEN1 patients demonstrates that most of the lesions from the MEN1 spectrum may be encountered during the two first decades of life. Therefore, following recent recommendations among presymptomatic patients is important keeping in mind that applying them in real life is always a challenge (Table 6).

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