Multiple endocrine neoplasia type 2 pathophysiology: Difference between revisions

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{{Multiple endocrine neoplasia type 2}}
{{Multiple endocrine neoplasia type 2}}
{{CMG}}; {{AE}} {{Ammu}}
{{CMG}}; {{AE}} {{Ammu}}
==Overview==
==Overview==
The progression to multiple endocrine neoplasia type 2 usually involves the [[Genetics|genetic]] [[Mutation|mutations]]. The pathogenesis of multiple endocrine neoplasia type 2 involves a mutation of the ''[[RET gene|RET]]'' [[gene]].
==Pathogenesis==
==Pathogenesis==
* The common feature among the three sub-types of MEN2 is a high propensity to develop medullary thyroid carcinoma.
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 2A===
* Multiple endocrine neoplasia type 2 (MEN2) (also known as "Pheochromocytoma and amyloid producing medullary thyroid carcinoma",<ref name="Bolognia" /> "PTC syndrome,"<ref name="Bolognia" /> and "Sipple syndrome"<ref name="Bolognia">{{cite book |author=Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. |title=Dermatology: 2-Volume Set |publisher=Mosby |location=St. Louis |year=2007 |pages= |isbn=1-4160-2999-0 }}</ref>) is a group of medical disorders associated with [[tumors]] of the [[endocrine system]].
* Multiple endocrine neoplasia type 2 (MEN2) generally occur in [[endocrine organ]]s (e.g. [[thyroid]], [[parathyroid]], and [[Adrenal gland|adrenals]]), but may also occur in [[endocrine]] [[tissues]] of organs not classically thought of as [[endocrine]].<ref name="Moline">{{cite journal | author = Moline J, Eng C. | title = Multiple endocrine neoplasia type 2: an overview. | journal = Genet Med. | year=2011 | volume=9 | issue=13 | pages=755–64 | pmid = 21552134 | doi =10.1097/GIM.0b013e318216cc6d}}</ref>
* They generally occur in endocrine organs (e.g. [[thyroid]], [[parathyroid]], and [[Adrenal gland|adrenals]]), but may also occur in endocrine tissues of organs not classically thought of as endocrine.<ref name=Moline>{{cite journal | author = Moline J, Eng C. | title = Multiple endocrine neoplasia type 2: an overview. | journal = Genet Med. | year=2011 | volume=9 | issue=13 | pages=755–64 | pmid = 21552134 | doi =10.1097/GIM.0b013e318216cc6d}}</ref>
* Although many different types of [[hormone]]-producing [[tumor]]s are associated with multiple endocrine neoplasia type 2, the most common manifestation is a form of [[thyroid]] [[cancer]] called [[thyroid cancer#medullary thyroid cancer (MTC)|medullary thyroid carcinoma]]. This [[tumor]] secretes an inactive [[hormone]] called [[calcitonin]]. <ref name="CoteGrubbs2015">{{cite journal|last1=Cote|first1=Gilbert J.|last2=Grubbs|first2=Elizabeth G.|last3=Hofmann|first3=Marie-Claude|title=Thyroid C-Cell Biology and Oncogenic Transformation|volume=204|year=2015|pages=1–39|issn=0080-0015|doi=10.1007/978-3-319-22542-5_1}}</ref>
* In MEN2A primary hyperparathyroidism occurs in only 10–30% and is usually diagnosed after the third decade of life. It can occur in children but this is rare. It may be the sole clinical manifestation of this syndrome but this is unusual.
*Many people with this disorder also develop [[pheochromocytoma]], which is a [[tumor]] of the [[adrenal gland]]s (located above each [[kidney]]) that can cause dangerously high [[blood pressure]]. In addition, overactivity of the [[parathyroid gland]] ([[hyperparathyroidism]]) occurs in some cases of [[multiple endocrine neoplasia type 2]]. [[Hyperparathyroidism]] disrupts the normal balance of [[calcium]] in the [[blood]], which can lead to [[kidney stones]], thinning of [[bone]]s, [[weakness]], and [[fatigue]].<ref name="KantorovichPacak2010">{{cite journal|last1=Kantorovich|first1=Vitaly|last2=Pacak|first2=Karel|title=Pheochromocytoma and Paraganglioma|volume=182|year=2010|pages=343–373|issn=00796123|doi=10.1016/S0079-6123(10)82015-1}}</ref>
* MEN2A associates medullary thyroid carcinoma with pheochromocytoma in about 20–50% of cases and with primary hyperparathyroidism in 5–20% of cases.
* In multiple endocrine neoplasia type 2, primary [[hyperparathyroidism]] occurs in only 10–30% and is usually diagnosed after the third decade of life. It can occur in children but this is rare. It may be the sole clinical manifestation of this syndrome but this is unusual.<ref name="WellsPacini2013">{{cite journal|last1=Wells|first1=Samuel A.|last2=Pacini|first2=Furio|last3=Robinson|first3=Bruce G.|last4=Santoro|first4=Massimo|title=Multiple Endocrine Neoplasia Type 2 and Familial Medullary Thyroid Carcinoma: An Update|journal=The Journal of Clinical Endocrinology & Metabolism|volume=98|issue=8|year=2013|pages=3149–3164|issn=0021-972X|doi=10.1210/jc.2013-1204}}</ref>
* In familial isolated medullary thyroid carcinoma the other components of the disease are absent.
* Multiple endocrine neoplasia type 2 associates [[medullary thyroid carcinoma]] with [[pheochromocytoma]] in about 20–50% of cases and with primary [[hyperparathyroidism]] in 5–20% of cases.<ref name="AlmeidaStratakis2010">{{cite journal|last1=Almeida|first1=Madson Q.|last2=Stratakis|first2=Constantine A.|title=Solid tumors associated with multiple endocrine neoplasias|journal=Cancer Genetics and Cytogenetics|volume=203|issue=1|year=2010|pages=30–36|issn=01654608|doi=10.1016/j.cancergencyto.2010.09.006}}</ref>
* Other components of the [[disease]] are absent in familial isolated [[medullary thyroid carcinoma]].<ref name="Niccoli-SireConte-Devolx2007">{{cite journal|last1=Niccoli-Sire|first1=P.|last2=Conte-Devolx|first2=B.|title=Néoplasies endocriniennes multiples de type 2|journal=Annales d'Endocrinologie|volume=68|issue=5|year=2007|pages=317–324|issn=00034266|doi=10.1016/j.ando.2007.04.005}}</ref>
 
===Multiple Endocrine Neoplasia type 2B===
===Multiple Endocrine Neoplasia type 2B===
* Multiple endocrine neoplasia type 2B (also known as MEN2B, Mucosal neuromata with endocrine tumors, Multiple endocrine neoplasia type 3, and Wagenmann–Froboese syndrome<ref name="Bolognia">{{cite book |author=Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. |title=Dermatology: 2-Volume Set |publisher=Mosby |location=St. Louis |year=2007 |pages=858 |isbn=1-4160-2999-0 |oclc= |doi= |accessdate=}}</ref>) is a genetic disease that causes multiple tumors on the mouth, eyes, and [[endocrine system|endocrine]] glands. It is the most severe type of [[multiple endocrine neoplasia]],<ref name=Carlson>{{cite journal  |vauthors=Carlson KM, Bracamontes J, Jackson CE, etal |title=Parent-of-origin effects in multiple endocrine neoplasia type 2B |journal=Am. J. Hum. Genet. |volume=55 |issue=6 |pages=1076–82 |date=December 1994 |pmid=7977365 |pmc=1918453 }}</ref> differentiated by the presence of benign oral and submucosal tumors in addition to endocrine malignancies.
* Multiple endocrine neoplasia type 2B is associated with [[medullary thyroid carcinoma]] and [[pheochromocytoma]] as well as with marfanoid habitus and with [[mucosal]] and [[digestive]] [[neurofibromatosis]].
* MEN2B associates medullary thyroid carcinoma with pheochromocytoma in 50% of cases, with marfanoid habitus and with mucosal and digestive neurofibromatosis.
{| style="border: 0px; font-size: 90%; margin: 3px;" align="center"
|+'''''Clinical features of multiple endocrine neoplasia syndrome'''''
! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Subtype}}
! style="background: #4479BA; width: 550px;" | {{fontcolor|#FFF|Medullary Thyroid Carcinoma}}
! style="background: #4479BA; width: 550px;" | {{fontcolor|#FFF|Pheochromocytoma}}
! style="background: #4479BA; width: 550px;" | {{fontcolor|#FFF|Parathyroid Disease}}
|-
! style="background: #F5F5F5;" | Multiple endocrine neoplasia type 2A
! style="background: #F5F5F5;" | 95%
! style="background: #F5F5F5;" | 50%
! style="background: #F5F5F5;" | 20% to 30%
|-
! style="background: #F5F5F5;" | Multiple endocrine neoplasia type 2B
! style="background: #F5F5F5;" | 100%
! style="background: #F5F5F5;" | 50%
! style="background: #F5F5F5;" | Uncommon
|-
! style="background: #F5F5F5;" | Familial medullary thyroid carcinoma
! style="background: #F5F5F5;" | 100%
! style="background: #F5F5F5;" | 0%
! style="background: #F5F5F5;" | 0%
|}


==Genetics==
===Genetics===
[[Image:autodominant2.jpg|thumb|left|Most cases of multiple endocrine neoplasia type 2 are inherited in an [[autosomal dominant]] pattern.]]
[[Image:autodominant2.jpg|thumb|center|500px|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]] gene. These cases occur in people with no history of the disorder in their family.
* 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 [[mutation]]s in the [[RET proto-oncogene|''RET'' proto-oncogene]]. These cases occur in people with no history of the disorder in their family.
* Germline mutations are responsible for sporadic MEN 2, while mutations in the cysteine residues in the exons of the RET protein product are common in familial MEN 2.
[[File:RET kinase domain.jpg|thumb|center|500px|RET kinase domain - [http://www.scielo.br/scielo.php?script=sci_abstract&pid=S1807-59322012001300014&lng=en&nrm=iso&tlng=en Source: Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2 (Clinics)]]]
* Most cases of MEN2 derive from a variation in the RET proto-oncogene, and are specific for cells of neural crest origin.
* Germline [[mutation]]s are responsible for sporadic multiple endocrine neoplasia type 2, while [[mutation]]s in the [[cysteine]] residues in the [[exon]]s of the [[RET gene|RET]] protein product are common in familial multiple endocrine neoplasia type 2.<ref name="WellsPacini20133">{{cite journal|last1=Wells|first1=Samuel A.|last2=Pacini|first2=Furio|last3=Robinson|first3=Bruce G.|last4=Santoro|first4=Massimo|title=Multiple Endocrine Neoplasia Type 2 and Familial Medullary Thyroid Carcinoma: An Update|journal=The Journal of Clinical Endocrinology & Metabolism|volume=98|issue=8|year=2013|pages=3149–3164|issn=0021-972X|doi=10.1210/jc.2013-1204}}</ref>
* The protein produced by the RET gene plays an important role in the TGF-beta (transforming growth factor beta) signaling system. Because the TGF-beta system operates in nervous tissues throughout the body, variations in the RET gene can have effects in nervous tissues throughout the body.
* The majority of multiple endocrine neoplasia type 2 [[Patient|patients]], derive from a variation in the [[RET proto-oncogene|''RET'' proto-oncogene]], and are specific for cells of [[neural crest]] origin.<ref name="MartuccielloLerone2012">{{cite journal|last1=Martucciello|first1=Giuseppe|last2=Lerone|first2=Margherita|last3=Bricco|first3=Lara|last4=Tonini|first4=Gian|last5=Lombardi|first5=Laura|last6=Del Rossi|first6=Carmine G|last7=Bernasconi|first7=Sergio|title=Multiple endocrine neoplasias type 2B and RET proto-oncogene|journal=Italian Journal of Pediatrics|volume=38|issue=1|year=2012|pages=9|issn=1824-7288|doi=10.1186/1824-7288-38-9}}</ref>
* The RET protooncogene is a 21-exon gene and encodes for a tyrosine kinase transmembrane receptor located on chromosome 10q11.2.<ref name="pmidhttp://dx.doi.org/10.1155/2012/705036">{{cite journal| author=Schmoldt A, Benthe HF, Haberland G| title=Digitoxin metabolism by rat liver microsomes. | journal=Biochem Pharmacol | year= 1975 | volume= 24 | issue= 17 | pages= 1639-41 | pmid=http://dx.doi.org/10.1155/2012/705036 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10  }} </ref>
* The [[RET proto-oncogene|''RET'' protooncogene]] is a 21-[[exon]] [[gene]] and encodes for a [[tyrosine kinase]] transmembrane receptor located on [[chromosome]] 10q11.2.<ref>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</ref>
* Four different ligands have so far been recognized: the glial cell-line derived neutrophilic factor (GDNF), neurturin (NTN), persepin (PNS) and artemin (ART). The interaction is mediated by a ligand-specific coreceptor (e.g., the GFRα-1 is the co-receptor for the GDNF).
* Four different ligands have so far been recognized: The [[glial cell line-derived neutrophilic factor]] (GDNF), [[neurturin]] (NTN), persepin (PNS) and [[artemin]] (ART). The interaction is mediated by a ligand-specific coreceptor (e.g., the GFRα-1 is the co-[[receptor]] for the GDNF).<ref name="SchmutzlerRoy2009">{{cite journal|last1=Schmutzler|first1=B.S.|last2=Roy|first2=S.|last3=Hingtgen|first3=C.M.|title=Glial cell line–derived neurotrophic factor family ligands enhance capsaicin-stimulated release of calcitonin gene-related peptide from sensory neurons|journal=Neuroscience|volume=161|issue=1|year=2009|pages=148–156|issn=03064522|doi=10.1016/j.neuroscience.2009.03.006}}</ref>
* The receptor is composed of an extracellular domain (EC), with a distal cadherin-like region and a juxtamembrane cystein-rich region, a transmembrane domain (TM) and an intracellular domain with tyroisine-kinase activity (TK).
* The receptor is composed of an extracellular domain (EC), with a distal [[cadherin]]-like region and a juxtamembrane [[cysteine]]-rich region, a transmembrane domain (TM) and an [[intracellular]] domain with tyrosine-kinase activity (TK).<ref name="De FalcoCarlomagno2017">{{cite journal|last1=De Falco|first1=Valentina|last2=Carlomagno|first2=Francesca|last3=Li|first3=Hong-yu|last4=Santoro|first4=Massimo|title=The molecular basis for RET tyrosine-kinase inhibitors in thyroid cancer|journal=Best Practice & Research Clinical Endocrinology & Metabolism|volume=31|issue=3|year=2017|pages=307–318|issn=1521690X|doi=10.1016/j.beem.2017.04.013}}</ref>
Table below summerizes specific RET codons and their functions.<ref name="pmidhttp://dx.doi.org/10.6061/clinics/2012(Sup01)14">{{cite journal| author=Schmoldt A, Benthe HF, Haberland G| title=Digitoxin metabolism by rat liver microsomes. | journal=Biochem Pharmacol | year= 1975 | volume= 24 | issue= 17 | pages= 1639-41 | pmid=http://dx.doi.org/10.6061/clinics/2012(Sup01)14 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10  }} </ref>


<br>
The table below summarizes specific ''RET'' codons and their functions.<ref name="pmid22584710">{{cite journal| author=Wagner SM, Zhu S, Nicolescu AC, Mulligan LM| title=Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2. | journal=Clinics (Sao Paulo) | year= 2012 | volume= 67 Suppl 1 | issue=  | pages= 77-84 | pmid=22584710 | doi= | pmc=PMC3328826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22584710  }} </ref><ref name="WellsPacini20132">{{cite journal|last1=Wells|first1=Samuel A.|last2=Pacini|first2=Furio|last3=Robinson|first3=Bruce G.|last4=Santoro|first4=Massimo|title=Multiple Endocrine Neoplasia Type 2 and Familial Medullary Thyroid Carcinoma: An Update|journal=The Journal of Clinical Endocrinology & Metabolism|volume=98|issue=8|year=2013|pages=3149–3164|issn=0021-972X|doi=10.1210/jc.2013-1204}}</ref>
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
 
{| style="border: 0px; font-size: 90%; margin: 3px;" align="center"
|+'''''Molecular effects of RET mutations in multiple endocrine neoplasia type2'''''
|+'''''Molecular effects of RET mutations in multiple endocrine neoplasia type2'''''
! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Mutation location}}
! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Mutation location}}
Line 35: Line 61:
! style="background: #4479BA; width: 550px;" | {{fontcolor|#FFF|Phenotype}}
! style="background: #4479BA; width: 550px;" | {{fontcolor|#FFF|Phenotype}}
|-
|-
! style="background: #DCDCDC;" rowspan=2 |Extracellular cystine rich location
! rowspan="2" style="background: #DCDCDC;" |Extracellular [[cysteine]] rich location
! style="background: #F5F5F5;" |
! style="background: #F5F5F5;" |
:c609
:c609
Line 44: Line 70:
! style="background: #F5F5F5;" |Helps to form teritiary structure with the help of disulfide bonds
! style="background: #F5F5F5;" |Helps to form teritiary structure with the help of disulfide bonds
! style="background: #F5F5F5;" |Alteration in protein folding and maturation
! style="background: #F5F5F5;" |Alteration in protein folding and maturation
! style="background: #F5F5F5;" |MEN 2A and FMTC
! style="background: #F5F5F5;" |Multiple endocrine neoplasia type 2A and familial [[medullary thyroid carcinoma]] (FMTC)
|-
|-
! style="background: #F5F5F5;" |c634
! style="background: #F5F5F5;" |c634
! style="background: #F5F5F5;" |Formation of intramolecular disulfide bonds
! style="background: #F5F5F5;" |Formation of intramolecular disulfide bonds
! style="background: #F5F5F5;" |Ligand independant dimerization of receptor molecules  
! style="background: #F5F5F5;" |[[Ligand]] independant dimerization of [[receptor]] molecules  
! style="background: #F5F5F5;" |MEN 2A
! style="background: #F5F5F5;" |Multiple endocrine neoplasia type 2A
|-
|-
! style="background: #DCDCDC;" rowspan=6 |Intracellular tyrosine kinase domain
! rowspan="6" style="background: #DCDCDC;" |Intracellular [[tyrosine kinase]] domain
! style="background: #F5F5F5;" |
! style="background: #F5F5F5;" |
:L790
:L790
:Y791
:Y791
! style="background: #F5F5F5;" |Terminal lobe of RET kinase
! style="background: #F5F5F5;" |Terminal lobe of ''[[RET proto-oncogene|RET]]'' kinase
! style="background: #F5F5F5;" |Affects ATP binding and interlobe flexibility
! style="background: #F5F5F5;" |Affects [[ATP]] binding and interlobe flexibility
! style="background: #F5F5F5;" |MEN 2A and FMTC
! style="background: #F5F5F5;" |Multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma (FMTC)
|-
|-
! style="background: #F5F5F5;" |
! style="background: #F5F5F5;" |
:E768
:E768
! style="background: #F5F5F5;" |Close proximity with ATP binding site
! style="background: #F5F5F5;" |Close proximity with [[ATP]] binding site
! style="background: #F5F5F5;" |Alters interactions within the region
! style="background: #F5F5F5;" |Alters interactions within the region
! style="background: #F5F5F5;" |FMTC
! style="background: #F5F5F5;" |Familial [[medullary thyroid carcinoma]] (FMTC)
|-
|-
! style="background: #F5F5F5;" |
! style="background: #F5F5F5;" |
:V804
:V804
! style="background: #F5F5F5;" |Gatekeeper residue that regulates access to ATP binding site
! style="background: #F5F5F5;" |Gatekeeper residue that regulates access to [[ATP]] binding site
! style="background: #F5F5F5;" |Alters interactions within the region
! style="background: #F5F5F5;" |Alters interactions within the region
! style="background: #F5F5F5;" |FMTC
! style="background: #F5F5F5;" |Familial [[medullary thyroid carcinoma]] (FMTC)
|-
|-
! style="background: #F5F5F5;" |
! style="background: #F5F5F5;" |
:S891
:S891
! style="background: #F5F5F5;" |C terminal lobe of kinase
! style="background: #F5F5F5;" |C terminal lobe of [[kinase]]
! style="background: #F5F5F5;" |Alters activation of loop conformation
! style="background: #F5F5F5;" |Alters activation of loop conformation
! style="background: #F5F5F5;" |MEN 2A and FMTC
! style="background: #F5F5F5;" |Multiple endocrine neoplasia type 2A and familial [[medullary thyroid carcinoma]] (FMTC)
|-
|-
! style="background: #F5F5F5;" |
! style="background: #F5F5F5;" |
Line 81: Line 107:
! style="background: #F5F5F5;" |Situated next to activated loop  
! style="background: #F5F5F5;" |Situated next to activated loop  
! style="background: #F5F5F5;" |Local conformational change
! style="background: #F5F5F5;" |Local conformational change
! style="background: #F5F5F5;" |MEN 2B
! style="background: #F5F5F5;" |Multiple endocrine neoplasia type 2B
|-
|-
! style="background: #F5F5F5;" |
! style="background: #F5F5F5;" |
:M918
:M918
! style="background: #F5F5F5;" |Substrate binding pocket of the kinase
! style="background: #F5F5F5;" |Substrate binding pocket of the kinase
! style="background: #F5F5F5;" |Alters protein conformation
! style="background: #F5F5F5;" |Alters [[protein]] conformation
! style="background: #F5F5F5;" |MEN 2B
! style="background: #F5F5F5;" |Multiple endocrine neoplasia type 2B
|}
|}
* MEN2 generally results from a gain-of-function variant of a RET gene. Other diseases, such as Hirschsprung disease, result from loss-of-function variants.  
* Multiple endocrine neoplasia type 2 generally results from a gain-of-function variant of a ''[[RET proto-oncogene|RET]]'' gene. Other [[disease]]s, such as [[Hirschsprung disease]], result from loss-of-function variants.<ref name="SchmutzlerRoy20092">{{cite journal|last1=Schmutzler|first1=B.S.|last2=Roy|first2=S.|last3=Hingtgen|first3=C.M.|title=Glial cell line–derived neurotrophic factor family ligands enhance capsaicin-stimulated release of calcitonin gene-related peptide from sensory neurons|journal=Neuroscience|volume=161|issue=1|year=2009|pages=148–156|issn=03064522|doi=10.1016/j.neuroscience.2009.03.006}}</ref>
* When inherited, multiple endocrine neoplasia type 2 is transmitted in an autosomal dominant pattern, which means affected people have one affected parent, and possibly-affected siblings and children. Some cases, however, result from spontaneous new mutations in the RET gene. These cases occur in people with no family history of the disorder. In MEN2B, for example, about half of all cases arise as spontaneous new mutations.
*Multiple endocrine neoplasia type 2 is transmitted in an [[autosomal dominant]]. Nevertheless, it can result from spontaneous new mutations in the [[RET gene|''RET'' gene]] with no family history of the disorder, as reported in some cases. For instance, among multiple endocrine neoplasia type 2B, spontaneous new [[mutation]]s were observed in about 50% of the total number of cases.
* Activating germline point mutations of the RET proto-oncogene are causative events in MEN 2A, MEN 2B, and 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.
* Activating germline [[point mutation]]s 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.<ref name="WellsPacini20134">{{cite journal|last1=Wells|first1=Samuel A.|last2=Pacini|first2=Furio|last3=Robinson|first3=Bruce G.|last4=Santoro|first4=Massimo|title=Multiple Endocrine Neoplasia Type 2 and Familial Medullary Thyroid Carcinoma: An Update|journal=The Journal of Clinical Endocrinology & Metabolism|volume=98|issue=8|year=2013|pages=3149–3164|issn=0021-972X|doi=10.1210/jc.2013-1204}}</ref>
* The following figue depicts the structure and mutation of RET receptor.<ref name="pmidhttp://dx.doi.org/10.6061/clinics/2012(Sup01)14">{{cite journal| author=Schmoldt A, Benthe HF, Haberland G| title=Digitoxin metabolism by rat liver microsomes. | journal=Biochem Pharmacol | year= 1975 | volume= 24 | issue= 17 | pages= 1639-41 | pmid=http://dx.doi.org/10.6061/clinics/2012(Sup01)14 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10 }} </ref>
* The following figure depicts the structure and mutation of RET receptor.<ref name="pmid22584710">{{cite journal| author=Wagner SM, Zhu S, Nicolescu AC, Mulligan LM| title=Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2. | journal=Clinics (Sao Paulo) | year= 2012 | volume= 67 Suppl 1 | issue= | pages= 77-84 | pmid=22584710 | doi= | pmc=PMC3328826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22584710 }} </ref>
[[File:Genetics of MEN 2.png|thumb|center|500px|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]]
[[File:Genetics of MEN 2.png|thumb|center|500px|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 - [http://www.scielo.br/scielo.php?script=sci_abstract&pid=S1807-59322012001300014&lng=en&nrm=iso&tlng=en Source: Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2 (Clinics)]]]


===RET Activation===
===RET Activation===
* Dimerization of RET gene mediated through formation of multicomponent complex. RET is activated by binding both a soluable ligand and a a non signaling extracellular co-receptor. RET activation leads to phosphorylation of multiple intracellular tyrosine kinase.
* Dimerization of [[RET proto-oncogene|''RET'' proto-oncogene]] mediated through formation of multicomponent complex. [[RET proto-oncogene|''RET'' proto-oncogene]] is activated by binding both a soluble ligand and a non signaling [[extracellular]] co-receptor. ''[[RET gene|RET]]'' activation leads to phosphorylation of multiple [[intracellular]] [[tyrosine kinase]].
[[File:Mutations specificities.jpg|thumb|center|500px|MEN type 2 mutations - [http://www.scielo.br/scielo.php?script=sci_abstract&pid=S1807-59322012001300014&lng=en&nrm=iso&tlng=en Source: Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2 (Clinics)]]]


==Associated Conditions==
==Associated Conditions==
Some of the diseases specific to the genes of multiple endocrine neoplasia type 2 are as follows.<ref name="pmidhttp://dx.doi.org/10.6061/clinics/2012(Sup01)14">{{cite journal| author=Schmoldt A, Benthe HF, Haberland G| title=Digitoxin metabolism by rat liver microsomes. | journal=Biochem Pharmacol | year= 1975 | volume= 24 | issue= 17 | pages= 1639-41 | pmid=http://dx.doi.org/10.6061/clinics/2012(Sup01)14 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10 }} </ref>
* Some of the [[disease]]s specific to the [[gene]]s of multiple endocrine neoplasia type 2 are as follows.<ref name="pmid22584710">{{cite journal| author=Wagner SM, Zhu S, Nicolescu AC, Mulligan LM| title=Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2. | journal=Clinics (Sao Paulo) | year= 2012 | volume= 67 Suppl 1 | issue= | pages= 77-84 | pmid=22584710 | doi= | pmc=PMC3328826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22584710 }} </ref>
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
{| style="border: 0px; font-size: 90%; margin: 3px;" align="center"
|+'''''Associated tumors'''''
|+'''''Associated tumors'''''
! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Subtype}}
! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Subtype}}
! style="background: #4479BA; width: 550px;" | {{fontcolor|#FFF|Associated diseases}}
! style="background: #4479BA; width: 550px;" | {{fontcolor|#FFF|Associated diseases}}
|-
|-
! style="background: #F5F5F5;" |MEN2A
! style="background: #F5F5F5;" |Multiple endocrine neoplasia type 2A 
! style="background: #F5F5F5;" |Cutaneous lichen amyloidosis, Hirschsprung disease
! style="background: #F5F5F5;" |Cutaneous lichen [[amyloidosis]], [[Hirschsprung disease]]
|-
|-
! style="background: #F5F5F5;" |MEN2B
! style="background: #F5F5F5;" |Multiple endocrine neoplasia type 2B
! style="background: #F5F5F5;" |Ganglioneuromatosis, marfanoid habitus
! style="background: #F5F5F5;" |Ganglioneuromatosis, marfanoid habitus
|-
|-
! style="background: #F5F5F5;" |FMTC
! style="background: #F5F5F5;" |Familial medullary thyroid carcinoma (FMTC)
! style="background: #F5F5F5;" |Rare diseases
! style="background: #F5F5F5;" |Rare diseases
|}
|}


==Gross Pathology==
===Gross Pathology===
<gallery>
<gallery>
Image:Bilateral pheo MEN2.jpg|ADRENAL GLAND: BILATERAL PHEOCHROMOCYTOMA Cross section of bilateral pheochromocytomas from a 30-year-old man with MEN syndrome type IIa. The right adrenal tumor weighed 168 g and the left 220 g. Note the distinct multinodular, multicentric pattern of growth on both sides
Image:Bilateral pheo MEN2.jpg|ADRENAL GLAND: BILATERAL PHEOCHROMOCYTOMA Cross section of bilateral pheochromocytomas from a 30-year-old man with MEN syndrome type IIa. The right adrenal tumor weighed 168 g and the left 220 g. Note the distinct multinodular, multicentric pattern of growth on both sides [https://upload.wikimedia.org/wikipedia/commons/5/5f/Bilateral_pheo_MEN2.jpg Source: Wikimedia Commons]
Image:Pheochromocytoma 03.jpeg|Pheochromocytoma, From the case <ref>"http://radiopaedia.org/cases/10816">rID: 10816</ref>
Image:Pheochromocytoma 03.jpeg|Pheochromocytoma, Image courtesy of Dr Frank Gaillard<ref name=radio02>Image courtesy of Dr Frank Gaillard. [http://www.radiopaedia.org Radiopaedia] (original file[http://radiopaedia.org/cases/10816‘’here’’]).[http://radiopaedia.org/licence Creative Commons BY-SA-NC]</ref>
Image:Pheochromocytoma 04.JPG|Pheochromocytoma, From the case <ref>"http://radiopaedia.org/cases/10816">rID: 10816</ref>
Image:Pheochromocytoma 04.JPG|Pheochromocytoma, Image courtesy of Dr Frank Gaillard<ref name=radio02>Image courtesy of Dr Frank Gaillard. [http://www.radiopaedia.org Radiopaedia] (original file[http://radiopaedia.org/cases/10816‘’here’’]).[http://radiopaedia.org/licence Creative Commons BY-SA-NC]</ref>
</gallery>
</gallery>


==Microscopic Pathology==
===Microscopic Pathology===
===Medullary Carcinoma of Thyroid===
====Medullary Carcinoma of Thyroid====
* Nests of C cells invading the basement membrane and infiltrating thyroid follicles.
* Nests of [[C cell]]s invading the [[basement membrane]] and infiltrating [[thyroid]] follicles
<gallery>
<gallery>
Image:MIcroscopic pathology of medullary thyroid cancer .jpg|High magnification micrograph of medullary thyroid carcinoma, abbreviated MTC. H&E stain. MTC can be remembered by the 3 Ms:aMyloid. Median node dissection. MEN 2A & MEN 2B. It typically stains with: Calcitonin. CEA. Chromogranin A. Multiple endocrine neoplasia 2A: Medullary thyroid carcinoma
Image:Pheochromocytoma histology.jpg|Pheochromocytoma, Case courtesy of Dr Andrew Ryan, [http://radiopaedia.org/ Radiopaedia.org From the case <a href="http://radiopaedia.org/cases/22683">rID: 22683]
Image:Pheochromocytoma high mag.jpg|Micrograph of a pheochromocytoma (at high magnification) showing the characteristic stippled (finely granular) chromatin. The chromatin pattern is sometimes referred to as "salt-and-pepper" chromatin
Image:Pheochromocytoma histology.jpg|Pheochromocytoma, Case courtesy of Dr Andrew Ryan, <ref>"http://radiopaedia.org/">Radiopaedia.org</a>. From the case <a href="http://radiopaedia.org/cases/22683">rID: 22683</ref>
</gallery>
</gallery>
===Histopathological Video===
====Video====
{{#ev:youtube|P2uPUbDPbuI}}
{{#ev:youtube|7yjxG3KmX98}}
{{#ev:youtube|crwGfnWKEZ8}}


==References==
==References==
{{reflist|2}}
{{reflist|2}}
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Latest revision as of 20:11, 6 July 2019

Multiple endocrine neoplasia type 2 Microchapters

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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

  • ADRENAL GLAND: BILATERAL PHEOCHROMOCYTOMA Cross section of bilateral pheochromocytomas from a 30-year-old man with MEN syndrome type IIa. The right adrenal tumor weighed 168 g and the left 220 g. Note the distinct multinodular, multicentric pattern of growth on both sides Source: Wikimedia Commons

    ADRENAL GLAND: BILATERAL PHEOCHROMOCYTOMA Cross section of bilateral pheochromocytomas from a 30-year-old man with MEN syndrome type IIa. The right adrenal tumor weighed 168 g and the left 220 g. Note the distinct multinodular, multicentric pattern of growth on both sides Source: Wikimedia Commons

  • Pheochromocytoma, Image courtesy of Dr Frank Gaillard[16]

    Pheochromocytoma, Image courtesy of Dr Frank Gaillard[16]

  • Pheochromocytoma, Image courtesy of Dr Frank Gaillard[16]

    Pheochromocytoma, Image courtesy of Dr Frank Gaillard[16]

Microscopic Pathology

Medullary Carcinoma of Thyroid

Histopathological Video

Video

{{#ev:youtube|P2uPUbDPbuI}}

{{#ev:youtube|7yjxG3KmX98}}

{{#ev:youtube|crwGfnWKEZ8}}

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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