Exp Clin Endocrinol Diabetes 2024; 132(01): 39-46
DOI: 10.1055/a-2212-7536

Impact of Early Diagnostic and Therapeutic Interventions and Clinical Course in Children and Adolescents with Multiple Endocrine Neoplasia Types 1 and 2

Ja Hye Kim
1   Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
Yena Lee
1   Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
Soojin Hwang
1   Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
Ji-Hee Yoon
1   Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
Gu-Hwan Kim
2   Medical Genetics Center, Asan Medical Center, Seoul, Republic of Korea
Han-Wook Yoo
1   Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
Jin-Ho Choi
1   Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
› Author Affiliations


Purpose Multiple endocrine neoplasia types 1 (MEN1) and 2 (MEN2) are inherited endocrine tumor syndromes caused by mutations in the MEN1 or RET genes. This study aimed to investigate clinical outcomes and molecular characteristics among children with MEN.

Methods This study included eight patients from seven unrelated families. Data on clinical course, biochemical findings, and radiologic studies were collected by retrospective chart review. All diagnoses were genetically confirmed by Sanger sequencing of MEN1 in three MEN1 patients and RET in four patients with MEN2A and one patient with MEN2B.

Results Three patients with MEN1 from two families presented with hypoglycemia at a mean age of 11±2.6 years. Four patients with MEN2A were genetically diagnosed at a mean of 3.0±2.2 years of age by family screening; one of them was prenatally diagnosed by chorionic villus sampling. Three patients with MEN2A underwent prophylactic thyroidectomy from 5 to 6 years of age, whereas one patient refused surgery. The patient with MEN2B presented with a tongue neuroma and medullary thyroid carcinoma at 6 years of age. Subsequently, he underwent a subtotal colectomy because of bowel perforation and submucosal ganglioneuromatosis at 18 years of age.

Conclusion This study described the relatively long clinical course of pediatric MEN with a mean follow-up duration of 7.5±3.8 years. Insulinoma was the first manifestation in children with MEN1. Early diagnosis by family screening during the asymptomatic period enabled early intervention. The patient with MEN2B exhibited the most aggressive clinical course.

Supplementary Material

Publication History

Received: 15 August 2023
Received: 23 October 2023

Accepted: 14 November 2023

Accepted Manuscript online:
16 November 2023

Article published online:
22 December 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References

  • 1 Al-Salameh A, Cadiot G, Calender A. et al. Clinical aspects of multiple endocrine neoplasia type 1. Nat Rev Endocrinol 2021; 17: 207-224
  • 2 Wells SA, Asa SL, Dralle H. et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015; 25: 567-610
  • 3 Marini F, Falchetti A, Del Monte F. et al. Multiple endocrine neoplasia type 2. Orphanet J Rare Dis 2006; 1: 45
  • 4 Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol 2014; 386: 2-15
  • 5 Singeisen H, Renzulli MM, Pavlicek V. et al. Multiple endocrine neoplasia type 4: a new member of the MEN family. Endocr Connect 2023; 12: e220411
  • 6 Kamilaris CDC, Stratakis CA. Multiple endocrine neoplasia type 1 (MEN1): An update and the significance of early genetic and clinical diagnosis. Front Endocrinol (Lausanne) 2019; 10: 339
  • 7 Matkar S, Thiel A, Hua X. Menin: a scaffold protein that controls gene expression and cell signaling. Trends Biochem Sci 2013; 38: 394-402
  • 8 Puñales MK, Graf H, Gross JL. et al. RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab 2003; 88: 2644-2649
  • 9 Wells SA, Pacini F, Robinson BG. et al. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab 2013; 98: 3149-3164
  • 10 Vannucci L, Marini F, Giusti F. et al. MEN1 in children and adolescents: Data from patients of a regional referral center for hereditary endocrine tumors. Endocrine 2018; 59: 438-448
  • 11 Kwon EB, Jeong HR, Shim YS. et al. Multiple endocrine neoplasia type 1 presenting as hypoglycemia due to insulinoma. J Korean Med Sci 2016; 31: 1003-1006
  • 12 Gonçalves TD, Toledo RA, Sekiya T. et al. Penetrance of functioning and nonfunctioning pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1 in the second decade of life. J Clin Endocrinol Metab 2014; 99: E89-E96
  • 13 Goudet P, Dalac A, Le Bras M. et al. MEN1 disease occurring before 21 years old: A 160-patient cohort study from the Groupe d'étude des Tumeurs Endocrines. J Clin Endocrinol Metab 2015; 100: 1568-1577
  • 14 Romanet P, Mohamed A, Giraud S. et al. UMD-MEN1 Database: An overview of the 370 MEN1 variants present in 1676 patients from the French population. J Clin Endocrinol Metab 2019; 104: 753-764
  • 15 Hogan AR, Zhuge Y, Perez EA. et al. Pediatric thyroid carcinoma: Incidence and outcomes in 1753 Patients. J Surg Res 2009; 156: 167-172
  • 16 Moline J, Eng C. Multiple endocrine neoplasia type 2: An overview. Genet Med 2011; 13: 755-764
  • 17 Lee HY, Kwon AR, Chae HW. et al. Two cases of multiple endocrine neoplasia type 2B, early diagnosis by genetic analysis and prophylactic total thyroidectomy. J Korean Soc Pediatr Endocrinol 2010; 15: 138-144
  • 18 Richards S, Aziz N, Bale S. et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17: 405-424
  • 19 Debelenko LV, Swalwell JI, Kelley MJ. et al. MEN1 gene mutation analysis of high-grade neuroendocrine lung carcinoma. Genes Chromosom Cancer 2000; 28: 58-65
  • 20 George J, Walter V, Peifer M. et al. Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nat Commun 2018; 9: 1048
  • 21 Kloos RT, Eng C, Evans DB. et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 2009; 19: 565-612
  • 22 Giannis D, Moris D, Karachaliou GS. et al. Insulinomas: from diagnosis to treatment. A review of the literature. J Buon 2020; 25: 1302-1314
  • 23 Pieterman CRC, Valk GD. Update on the clinical management of multiple endocrine neoplasia type 1. Clin Endocrinol (Oxf) 2022; 97: 409-423
  • 24 Zhang X, Jia H, Li F. et al. Ectopic insulinoma diagnosed by 68Ga-Exendin-4 PET/CT: A case report and review of literature. Medicine. 2021. 100. e25076
  • 25 Beek DJ, Nell S, Verkooijen HM. et al. Surgery for multiple endocrine neoplasia type 1-related insulinoma: Long-term outcomes in a large international cohort. Br J Surg 2020; 107: 1489-1499
  • 26 Werner C, Winkens T, Freesmeyer M. Splenic scintigraphy for further differentiation of unclear 68Ga-DOTATOC-PET/CT findings: Strengths and limitations. J Med Imaging Radiat Oncol 2016; 60: 365-369
  • 27 Gezer E, Çetinarslan B, Karakaya D. et al. Differentiation of insulinoma from accessory spleen by 99mTc-labelled heat-denaturated red blood cell scintigraphy: Case report. BMC Endocr Disord 2021; 21: 6
  • 28 Kornaczewski Jackson ER, Pointon OP, Bohmer R. et al. Utility of FDG-PET imaging for risk stratification of pancreatic neuroendocrine tumors in MEN1. J Clin Endocrinol Metab 2017; 102: 1926-1933
  • 29 Sadowski SM, Millo C, Cottle-Delisle C. et al. Results of (68)Gallium-DOTATATE PET/CT scanning in patients with multiple endocrine neoplasia type 1. J Am Coll Surg 2015; 221: 509-517
  • 30 Kluijfhout WP, van Beek DJ, Verrijn Stuart AA. et al. Postoperative complications after prophylactic thyroidectomy for very young patients with multiple endocrine neoplasia type 2: Retrospective cohort analysis. Medicine (Baltimore) 2015; 94: e1108
  • 31 Matsushita R, Nagasaki K, Ayabe T. et al. Present status of prophylactic thyroidectomy in pediatric multiple endocrine neoplasia 2: A nationwide survey in Japan 1997–2017. J Pediatr Endocrinol Metab 2019; 32: 585-595
  • 32 Maciel RMB, Maia AL. Global endocrinolgy: Geographical variation in the profile of RET variants in patients with medullary thyroid cancer: A comprehensive review. Eur J Endocrinol 2022; 186: R15-R30
  • 33 Maciel RMB, Camacho CP, Assumpção LVM. et al. Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: The BrasMEN study. Endocr Connect 2019; 8: 289-298
  • 34 Thakker RV, Newey PJ, Walls GV. et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 2012; 97: 2990-3011
  • 35 Stenman A, Zedenius J, Juhlin CC. Over-diagnosis of potential malignant behavior in MEN 2A-associated pheochromocytomas using the PASS and GAPP algorithms. Langenbeck's Arch Surg 2018; 403: 785-790
  • 36 Brauckhoff M, Gimm O, Weiss CL. et al. Multiple endocrine neoplasia 2B syndrome due to codon 918 mutation: Clinical manifestation and course in early and late onset disease. World J Surg 2004; 28: 1305-1311
  • 37 Gfroerer S, Theilen T-M, Fiegel H. et al. Identification of intestinal ganglioneuromatosis leads to early diagnosis of MEN2B: Role of rectal biopsy. J Pediatr Surg 2017; 52: 1161-1165
  • 38 Castinetti F, Waguespack SG, Machens A. et al. Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: An international, multicentre, retrospective study. Lancet Diabetes Endocrinol 2019; 7: 213-220
  • 39 Rosenthal MS, Diekema DS. Pediatric ethics guidelines for hereditary medullary thyroid cancer. Int J Pediatr Endocrinol 2011; 2011: 847603-847603
  • 40 van den Broek MFM, de Laat JM, van Leeuwaarde RS. et al. The management of neuroendocrine tumors of the lung in MEN1: Results from the Dutch MEN1 study group. J Clin Endocrinol Metab 2021; 106: e1014-e1027
  • 41 Newey PJ, Newell-Price J. MEN1 surveillance guidelines: Time to (re)think?. J Endocr Soc 2022; 6: bvac001
  • 42 Ye L, Wang W, Ospina NS. et al. Clinical features and prognosis of thymic neuroendocrine tumours associated with multiple endocrine neoplasia type 1: A single-centre study, systematic review and meta-analysis. Clin Endocrinol (Oxf) 2017; 87: 706-716
  • 43 Elisei R, Romei C, Cosci B. et al. RET genetic screening in patients with medullary thyroid cancer and their relatives: Experience with 807 individuals at one center. J Clin Endocrinol Metab 2007; 92: 4725-4729