Multiple endocrine neoplasia type 2 pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [3]

Overview

The progression to multiple endocrine neoplasia type 2 usually involves the genetic mutations. The pathogenesis of multiple endocrine neoplasia type 2 involves a mutation of the RET gene.

Pathogenesis

The common feature among the three subtypes of multiple endocrine neoplasia type 2 is a high propensity to develop medullary thyroid carcinoma.

Multiple Endocrine Neoplasia type 2A

Multiple Endocrine Neoplasia type 2B

Clinical features of multiple endocrine neoplasia syndrome
Subtype Medullary Thyroid Carcinoma Pheochromocytoma Parathyroid Disease
Multiple endocrine neoplasia type 2A 95% 50% 20% to 30%
Multiple endocrine neoplasia type 2B 100% 50% Uncommon
Familial medullary thyroid carcinoma 100% 0% 0%

Genetics

Autosomal dominent pattern of inheritance - By nih.gov, Public Domain, https://commons.wikimedia.org/w/index.php?curid=1098109
  • Most cases of multiple endocrine neoplasia type 2 are inherited in an autosomal dominant pattern, which means affected people may have affected siblings and relatives in successive generations (such as parents and children). An affected person usually has one parent with the condition. Some cases, however, result from new mutations in the RET proto-oncogene. These cases occur in people with no history of the disorder in their family.
RET kinase domain - Source: Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2 (Clinics)

The table below summarizes specific RET codons and their functions.[12][13]

Molecular effects of RET mutations in multiple endocrine neoplasia type2
Mutation location RET codons Function of wild type codon Mutated effects Phenotype
Extracellular cysteine rich location
c609
c611
c618
c620
c630
Helps to form teritiary structure with the help of disulfide bonds Alteration in protein folding and maturation Multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma (FMTC)
c634 Formation of intramolecular disulfide bonds Ligand independant dimerization of receptor molecules Multiple endocrine neoplasia type 2A
Intracellular tyrosine kinase domain
L790
Y791
Terminal lobe of RET kinase Affects ATP binding and interlobe flexibility Multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma (FMTC)
E768
Close proximity with ATP binding site Alters interactions within the region Familial medullary thyroid carcinoma (FMTC)
V804
Gatekeeper residue that regulates access to ATP binding site Alters interactions within the region Familial medullary thyroid carcinoma (FMTC)
S891
C terminal lobe of kinase Alters activation of loop conformation Multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma (FMTC)
A883
Situated next to activated loop Local conformational change Multiple endocrine neoplasia type 2B
M918
Substrate binding pocket of the kinase Alters protein conformation Multiple endocrine neoplasia type 2B
  • Multiple endocrine neoplasia type 2 generally results from a gain-of-function variant of a RET gene. Other diseases, such as Hirschsprung disease, result from loss-of-function variants.[14]
  • Multiple endocrine neoplasia type 2 is transmitted in an autosomal dominant. Nevertheless, it can result from spontaneous new mutations in the RET gene with no family history of the disorder, as reported in some cases. For instance, among multiple endocrine neoplasia type 2B, spontaneous new mutations were observed in about 50% of the total number of cases.
  • Activating germline point mutations of the RET proto-oncogene are causative events in multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, and familial medullary thyroid carcinoma (FMTC). RET mutations have been found to be widely distributed not only among the 5 cysteine codons 609, 611, 618, 620, and 634 but also in other noncysteine codons, such as codon 804 in exon 14, codon 883 in exon 15, and others.[15]
  • The following figure depicts the structure and mutation of RET receptor.[12]
Structure, activation and oncogenic mutation of RET receptor. Figure A depicts location of oncogenic mutations of RET recpetor. RET protein has cystine rich extracellular domain, cadherin homology domain, transmembrane domain and an intracellular tyrosine kinase domain. FIgure B depicts RET activation - Source: Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2 (Clinics)

RET Activation

MEN type 2 mutations - Source: Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2 (Clinics)

Associated Conditions

  • Some of the diseases specific to the genes of multiple endocrine neoplasia type 2 are as follows.[12]
Associated tumors
Subtype Associated diseases
Multiple endocrine neoplasia type 2A Cutaneous lichen amyloidosis, Hirschsprung disease
Multiple endocrine neoplasia type 2B Ganglioneuromatosis, marfanoid habitus
Familial medullary thyroid carcinoma (FMTC) Rare diseases

Gross Pathology

Microscopic Pathology

Medullary Carcinoma of Thyroid

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References

  1. Moline J, Eng C. (2011). "Multiple endocrine neoplasia type 2: an overview". Genet Med. 9 (13): 755–64. doi:10.1097/GIM.0b013e318216cc6d. PMID 21552134.
  2. Cote, Gilbert J.; Grubbs, Elizabeth G.; Hofmann, Marie-Claude (2015). "Thyroid C-Cell Biology and Oncogenic Transformation". 204: 1–39. doi:10.1007/978-3-319-22542-5_1. ISSN 0080-0015.
  3. Kantorovich, Vitaly; Pacak, Karel (2010). "Pheochromocytoma and Paraganglioma". 182: 343–373. doi:10.1016/S0079-6123(10)82015-1. ISSN 0079-6123.
  4. Wells, Samuel A.; Pacini, Furio; Robinson, Bruce G.; Santoro, Massimo (2013). "Multiple Endocrine Neoplasia Type 2 and Familial Medullary Thyroid Carcinoma: An Update". The Journal of Clinical Endocrinology & Metabolism. 98 (8): 3149–3164. doi:10.1210/jc.2013-1204. ISSN 0021-972X.
  5. Almeida, Madson Q.; Stratakis, Constantine A. (2010). "Solid tumors associated with multiple endocrine neoplasias". Cancer Genetics and Cytogenetics. 203 (1): 30–36. doi:10.1016/j.cancergencyto.2010.09.006. ISSN 0165-4608.
  6. Niccoli-Sire, P.; Conte-Devolx, B. (2007). "Néoplasies endocriniennes multiples de type 2". Annales d'Endocrinologie. 68 (5): 317–324. doi:10.1016/j.ando.2007.04.005. ISSN 0003-4266.
  7. Wells, Samuel A.; Pacini, Furio; Robinson, Bruce G.; Santoro, Massimo (2013). "Multiple Endocrine Neoplasia Type 2 and Familial Medullary Thyroid Carcinoma: An Update". The Journal of Clinical Endocrinology & Metabolism. 98 (8): 3149–3164. doi:10.1210/jc.2013-1204. ISSN 0021-972X.
  8. Martucciello, Giuseppe; Lerone, Margherita; Bricco, Lara; Tonini, Gian; Lombardi, Laura; Del Rossi, Carmine G; Bernasconi, Sergio (2012). "Multiple endocrine neoplasias type 2B and RET proto-oncogene". Italian Journal of Pediatrics. 38 (1): 9. doi:10.1186/1824-7288-38-9. ISSN 1824-7288.
  9. C. Romei, E. Pardi, F. Cetani, and R. Elisei, “Genetic and Clinical Features of Multiple Endocrine Neoplasia Types 1 and 2,” Journal of Oncology, vol. 2012, Article ID 705036, 15 pages, 2012. doi:10.1155/2012/705036
  10. Schmutzler, B.S.; Roy, S.; Hingtgen, C.M. (2009). "Glial cell line–derived neurotrophic factor family ligands enhance capsaicin-stimulated release of calcitonin gene-related peptide from sensory neurons". Neuroscience. 161 (1): 148–156. doi:10.1016/j.neuroscience.2009.03.006. ISSN 0306-4522.
  11. De Falco, Valentina; Carlomagno, Francesca; Li, Hong-yu; Santoro, Massimo (2017). "The molecular basis for RET tyrosine-kinase inhibitors in thyroid cancer". Best Practice & Research Clinical Endocrinology & Metabolism. 31 (3): 307–318. doi:10.1016/j.beem.2017.04.013. ISSN 1521-690X.
  12. 12.0 12.1 12.2 Wagner SM, Zhu S, Nicolescu AC, Mulligan LM (2012). "Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2". Clinics (Sao Paulo). 67 Suppl 1: 77–84. PMC 3328826. PMID 22584710.
  13. Wells, Samuel A.; Pacini, Furio; Robinson, Bruce G.; Santoro, Massimo (2013). "Multiple Endocrine Neoplasia Type 2 and Familial Medullary Thyroid Carcinoma: An Update". The Journal of Clinical Endocrinology & Metabolism. 98 (8): 3149–3164. doi:10.1210/jc.2013-1204. ISSN 0021-972X.
  14. Schmutzler, B.S.; Roy, S.; Hingtgen, C.M. (2009). "Glial cell line–derived neurotrophic factor family ligands enhance capsaicin-stimulated release of calcitonin gene-related peptide from sensory neurons". Neuroscience. 161 (1): 148–156. doi:10.1016/j.neuroscience.2009.03.006. ISSN 0306-4522.
  15. Wells, Samuel A.; Pacini, Furio; Robinson, Bruce G.; Santoro, Massimo (2013). "Multiple Endocrine Neoplasia Type 2 and Familial Medullary Thyroid Carcinoma: An Update". The Journal of Clinical Endocrinology & Metabolism. 98 (8): 3149–3164. doi:10.1210/jc.2013-1204. ISSN 0021-972X.
  16. 16.0 16.1 Image courtesy of Dr Frank Gaillard. Radiopaedia (original file[1]).Creative Commons BY-SA-NC


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