Wielogruczolakowatość endokrynna typu 2 (men 2)
Epidemiologia
Wielogruczolakowatość endokrynna typu 2 (MEN 2) to rzadki, autosomalnie dominujący zespół nowotworowy, charakteryzujący się wysoką penetracją mutacji genu RET, prowadzącą do niemal 100% ryzyka rozwoju raka rdzeniastego tarczycy (MTC). MEN 2 dzieli się na podtypy MEN 2A (95% przypadków) i MEN 2B (5%), z różnicami w wieku wystąpienia i agresywności nowotworów. MEN 2A manifestuje się zwykle w dorosłości, z MTC rozwijającym się do 50. roku życia u 50% pacjentów, natomiast MEN 2B cechuje się wczesnym, agresywnym przebiegiem MTC, często już w pierwszych dwóch dekadach życia. Guzy chromochłonne nadnerczy występują u 40-50% pacjentów z MEN 2B i do 50% z MEN 2A, zwykle w drugiej lub trzeciej dekadzie życia. Diagnostyka opiera się na badaniach genetycznych w kierunku mutacji RET, które umożliwiają wczesne wykrycie nosicieli i wdrożenie profilaktycznej tyroidektomii, kluczowej dla poprawy rokowania.
Wielogruczolakowatość endokrynna typu 2 (MEN 2) – Epidemiologia
Wielogruczolakowatość endokrynna typu 2 (MEN 2) jest rzadkim zespołem nowotworowym, charakteryzującym się przede wszystkim występowaniem guzów w gruczołach dokrewnych: tarczycy, nadnerczach i przytarczycach. Częstość występowania wszystkich typów MEN 2 na świecie szacuje się na około 1 na 35 000 osób, natomiast w Stanach Zjednoczonych wynosi od 1 na 30 000 do 1 na 50 000 osób123. Epidemiologia MEN 2B nie jest dokładnie określona, a jej częstość występowania szacuje się na od 1 na 600 000 do 1 na 4 miliony osób1.
Warto zauważyć, że rzeczywista częstość występowania zespołu MEN 2 może być niedoszacowana, ponieważ choroba może pozostawać nierozpoznana u części pacjentów4. MEN 2 dzieli się na dwa główne podtypy: MEN 2A i MEN 2B. MEN 2A, który stanowi około 95% wszystkich przypadków MEN 2, jest znacznie częstszy niż MEN 2B (stanowiący około 5% przypadków)567. W badaniu przeprowadzonym w Danii zaobserwowano wyższą częstość występowania MEN 2A, szacowaną na 1 na 40 000, co prawdopodobnie wynika z efektu założyciela dla mutacji C611Y w tym kraju8.
Wiek wystąpienia objawów i penetracja genu
MEN 2 może dotykać wszystkie grupy wiekowe, a objawy mogą pojawiać się już we wczesnym dzieciństwie (szczególnie w przypadku MEN 2B) lub dopiero w wieku dorosłym (głównie w MEN 2A)5. U pacjentów z MEN 2A, u 50% osób z mutacjami genu RET choroba rozwija się do 50. roku życia, a u 70% do 70. roku życia3. Natomiast w przypadku MEN 2B, rak rdzeniasty tarczycy (MTC) może być wykryty krótko po urodzeniu3.
Penetracja genu (prawdopodobieństwo wystąpienia objawów klinicznych u osób z mutacją) jest bardzo wysoka w przypadku MEN 2. W MEN 2A penetracja wynosi około 95%, natomiast w przypadku MEN 2B i rodzinnego raka rdzeniastego tarczycy (FMTC) jest prawie 100%7. Ryzyko rozwoju raka rdzeniastego tarczycy w ciągu życia wynosi prawie 100% u wszystkich osób z wariantami MEN 29.
Rozkład zachorowań w zależności od płci i wieku
MEN 2 dotyka w równym stopniu mężczyzn i kobiety1011. Szczyt zachorowań na raka rdzeniastego tarczycy w MEN 2A przypada na trzecią dekadę życia, jednak u dzieci MTC może wystąpić już przed 6. rokiem życia, a w niektórych przypadkach nawet u 2-letnich dzieci12. W przypadku MEN 2B, rak rdzeniasty tarczycy rozwija się wcześniej i ma bardziej agresywny przebieg niż w MEN 2A, zazwyczaj w pierwszej i drugiej dekadzie życia13.
Guzy chromochłonne nadnerczy (pheochromocytoma) i nadczynność przytarczyc częściej występują u osób dorosłych. U pacjentów z MEN 2A, do 50% osób może rozwinąć guzy chromochłonne w drugiej lub trzeciej dekadzie życia12. W przypadku MEN 2B, guzy chromochłonne występują u 40-50% pacjentów13.
Czynniki ryzyka wystąpienia MEN 2
Głównym czynnikiem ryzyka rozwoju MEN 2 jest występowanie mutacji w genie RET. MEN 2 jest dziedziczone w sposób autosomalny dominujący z wysoką penetracją146. Oznacza to, że osoby posiadające mutację genu RET mają 50% szans na przekazanie jej swoim dzieciom, niezależnie od płci1516.
Około 75% przypadków MEN 2B to przypadki sporadyczne (z mutacją RET powstającą de novo), podczas gdy 25% to przypadki rodzinne6. Podobnie, około 5% mutacji w MEN 2A i 50% mutacji w MEN 2B to mutacje de novo7. Oznacza to, że część pacjentów może być pierwszymi osobami w swoich rodzinach z tym zaburzeniem16.
Rodzaj mutacji w genie RET wpływa na fenotyp kliniczny i agresywność raka rdzeniastego tarczycy. Dlatego Amerykańskie Towarzystwo Tyreologiczne (ATA) sklasyfikowało mutacje RET w kategoriach ryzyka: najwyższego ryzyka (HST), wysokiego ryzyka (H) i umiarkowanego ryzyka (MOD)6. Ta klasyfikacja pomaga w określeniu optymalnego postępowania terapeutycznego i nadzoru nad pacjentami.
Nadzór i screening w MEN 2
Badania genetyczne
Badania genetyczne odgrywają kluczową rolę w diagnostyce i zarządzaniu MEN 2. Amerykańskie Towarzystwo Tyreologiczne oraz National Comprehensive Cancer Network zalecają wykonanie badań DNA w kierunku mutacji genu RET u wszystkich osób z rakiem rdzeniastym tarczycy17. Badania te pozwalają na wczesne wykrycie nosicieli mutacji przed pojawieniem się objawów klinicznych18.
Jeśli u członka rodziny zostanie zdiagnozowane MEN 2, zaleca się badania genetyczne u wszystkich krewnych pierwszego stopnia (rodziców, rodzeństwa, dzieci), ponieważ mają oni do 50% ryzyka odziedziczenia patogennego wariantu19. Badania te są szczególnie ważne, ponieważ wczesne wykrycie umożliwia profilaktyczne usunięcie tarczycy, co daje największą szansę na wyleczenie20.
Jeśli badania genetyczne nie wykażą zmian genetycznych u członków rodziny, zazwyczaj nie są potrzebne dalsze badania przesiewowe. Jednak należy pamiętać, że badania genetyczne nie wykrywają wszystkich zmian genetycznych związanych z MEN 2. W przypadku osób, u których nie wykryto MEN 2, ale istnieje takie podejrzenie, zaleca się regularne badania krwi i obrazowe w celu monitorowania pod kątem objawów choroby16.
Monitorowanie pacjentów z MEN 2
Osoby z rozpoznanym MEN 2 wymagają dożywotniego monitorowania przez endokrynologa21. Zalecenia dotyczące badań przesiewowych zależą od konkretnego rodzaju mutacji RET i szacowanego ryzyka rozwoju nowotworów22.
- Coroczny pomiar stężenia kalcytoniny w surowicy u osób, które nie miały profilaktycznej tyroidektomii oraz w celu wykrycia resztkowego lub nawrotowego raka rdzeniastego tarczycy po tyroidektomii, nawet jeśli tyroidektomia została wykonana przed pojawieniem się biochemicznych dowodów choroby.
- Coroczne badanie wolnych metanefryn w osoczu lub 24-godzinne badanie moczu na frakcjonowane metanefryny u osób z patogennym wariantem genu RET, u których początkowe wyniki badań przesiewowych są negatywne dla guza chromochłonnego.
- Coroczne badanie skorygowanego wapnia w albuminie lub wapnia zjonizowanego u osób z MEN 2A/FMTC, u których początkowe wyniki badań przesiewowych są negatywne dla nadczynności przytarczyc.
Amerykańskie Towarzystwo Tyreologiczne zaleca rozpoczęcie badań przesiewowych w kierunku guza chromochłonnego w wieku 11 lat u pacjentów z wariantami patogennymi RET kategorii ATA-HST lub ATA-H oraz w wieku 16 lat u pacjentów z wariantami patogennymi RET kategorii ATA-MOD1724. Podobnie zaleca się badania przesiewowe w kierunku nadczynności przytarczyc od 11. roku życia u nosicieli wariantów patogennych ATA-HST i ATA-H oraz od 16. roku życia u nosicieli wariantów patogennych ATA-MOD17.
Badania przesiewowe w kierunku guza chromochłonnego obejmują pomiar wolnych metanefryn w osoczu i normetanefryn lub 24-godzinne badanie moczu na metanefryny i normetanefryny. Obrazowanie nadnerczy za pomocą tomografii komputerowej lub rezonansu magnetycznego jest wskazane u pacjentów z pozytywnymi wynikami biochemicznymi22.
Nadzór pooperacyjny
Nawet po całkowitej resekcji guzów, pacjenci z MEN 2 wymagają dalszego monitorowania. Około 50% pacjentów z rakiem rdzeniastym tarczycy, którzy przeszli całkowitą tyroidektomię i wycięcie węzłów chłonnych szyi, ma nawrotową chorobę25. Dlatego kontynuacja monitorowania pod kątem resztkowego lub nawrotowego raka rdzeniastego tarczycy jest wskazana po tyroidektomii, nawet jeśli tyroidektomia została wykonana przed pojawieniem się biochemicznych dowodów choroby25.
Zalecane odstępy nadzoru dla pacjentów z guzami chromochłonnymi po całkowitej resekcji obejmują26:
- Wywiad, badanie fizykalne z pomiarem ciśnienia krwi i markery nowotworowe mierzone po 3-12 miesiącach, następnie co 6 miesięcy przez pierwsze 3 lata i corocznie przez okres do 10 lat.
- Można rozważyć tomografię komputerową klatki piersiowej z kontrastem lub bez, tomografię komputerową lub rezonans magnetyczny jamy brzusznej/miednicy z kontrastem lub FDG-PET/CT.
Znaczenie wczesnego wykrywania i profilaktyki
Wczesne wykrycie MEN 2 jest kluczowe, ponieważ choroba często wiąże się z wysokim ryzykiem rozwoju nowotworów, które mogą wystąpić w młodszym wieku niż oczekiwano4. Doskonałe rokowanie w przypadku raka rdzeniastego tarczycy rozpoznanego we wczesnym stadium podkreśla znaczenie wczesnej diagnostyki sporadycznego i dziedzicznego raka rdzeniastego tarczycy14.
Profilaktyczna tyroidektomia jest podstawowym środkiem zapobiegawczym u osób z zidentyfikowaną mutacją germinalną RET25. Zalecany wiek przeprowadzenia profilaktycznej tyroidektomii zależy od konkretnej mutacji RET i związanego z nią ryzyka. Amerykańskie Towarzystwo Onkologiczne zaleca usunięcie tarczycy27:
- W ciągu pierwszych sześciu miesięcy życia u osób z MEN 2B
- W wieku od 5 do 10 lat u osób z MEN 2A i FMTC
Wczesne wykrycie i leczenie guzów chromochłonnych jest również istotne. Jeśli guzy te zostaną wykryte wcześnie, są łatwe do leczenia. Jednak nieleczone mogą być potencjalnie śmiertelne z powodu niebezpiecznie wysokiego ciśnienia krwi, które może wystąpić podczas wypadków, operacji, porodu lub innych fizycznie stresujących sytuacji27.
Rokowanie w MEN 2 zależy od stadium, w którym zostaje rozpoznany rak rdzeniasty tarczycy, oraz od skuteczności początkowego leczenia chirurgicznego. Wczesna diagnoza i całkowita początkowa resekcja guzów zwiększają oczekiwaną długość życia6. Dlatego tak ważne jest wczesne wykrycie i profilaktyczne leczenie chirurgiczne u nosicieli mutacji RET.
Znaczenie kliniczne nadzoru i badań przesiewowych
Nadzór i badania przesiewowe w MEN 2 mają kluczowe znaczenie dla wczesnego wykrywania i leczenia powiązanych nowotworów. Badania genetyczne umożliwiają identyfikację osób z wysokim ryzykiem rozwoju choroby, co pozwala na wdrożenie odpowiednich strategii nadzoru i profilaktyki22.
Pacjenci z MEN 2 powinni być pod opieką specjalistycznych ośrodków, pod kierunkiem doświadczonego zespołu multidyscyplinarnego28. Regularne badania przesiewowe pozwalają na wykrycie nowotworów we wczesnym i dającym się opanować stadium oraz uniknięcie nieodwracalnych lub poważnych powikłań medycznych29.
Dzieci zdiagnozowane z MEN 2 będą potrzebowały dożywotniej opieki kontrolnej i badań przesiewowych w kierunku nowotworów4. W przypadkach, gdy rodzice odmawiają ujawnienia informacji i badania dziecka, może być konieczna interwencja prawna, ponieważ dziecko jest narażone na wysokie ryzyko odziedziczenia złośliwego guza30.
Osiągnięcia w zakresie badań genetycznych i lepsze zrozumienie naturalnego przebiegu choroby doprowadziły do zmiany paradygmatu w leczeniu MEN 2: od usuwania narządów docelowych kosztem większej chorobowości operacyjnej do ścisłego nadzoru biochemicznego i ukierunkowanej resekcji guzów nadnerczy i hiperplastycznych gruczołów przytarczycznych31. Ta zmiana podejścia daje nadzieję, że śmierć i poważne zachorowania z powodu tej rzadkiej choroby mogą zostać wyeliminowane w naszym życiu31.
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Materiały źródłowe
- #1 Multiple Endocrine Neoplasias Type 2 – StatPearls – NCBI Bookshelfhttps://www.ncbi.nlm.nih.gov/books/NBK519054/
Multiple endocrine neoplasia type 2 (MEN 2) is a hereditary cancer syndrome associated primarily with tumors of the adrenal gland, thyroid and parathyroid. […] The prevalence of all MEN2 worldwide is 1 in 35,000, while in the United States, it is 1 in 30,000 to 50,000. The epidemiology of MEN2B is unknown. The prevalence of MEN2B is estimated to be between 1 in 600,000 to 1 in 4 million.
- #2 Multiple Endocrine Neoplasia Type 2 – GeneReviews® – NCBI Bookshelfhttps://www.ncbi.nlm.nih.gov/books/NBK1257/
Multiple endocrine neoplasia type 2 (MEN2) includes the following phenotypes: MEN2A, familial medullary thyroid carcinoma (FMTC, which may be a variant of MEN2A), and MEN2B. […] The diagnosis of MEN2 is established in a proband who fulfills existing clinical diagnostic criteria or by identification of a heterozygous germline gain-of-function variant in RET on molecular genetic testing. Molecular genetic testing is recommended in all individuals with a clinical diagnosis due to genotype-specific surveillance and treatment recommendations and to allow family studies. […] Annual measurement of serum calcitonin concentration in those who have not had prophylactic thyroidectomy and to detect residual or recurrent MTC after thyroidectomy, even if thyroidectomy was performed prior to biochemical evidence of disease. Annual plasma free metanephrines or 24-hour urine for fractionated metanephrines for those with a germline RET pathogenic variant whose initial screening results are negative for pheochromocytoma. Annual albumin-corrected calcium or ionized calcium for individuals with MEN2A/FMTC whose initial screening results are negative for hyperparathyroidism. Age of initiation of surveillance for pheochromocytoma and hyperparathyroidism is determined by the specific germline RET pathogenic variant identified. […] The prevalence of MEN2 has been estimated at 1:35,000.
- #3 Multiple Endocrine Neoplasia Type 2 (MEN2): Practice Essentials, Pathophysiology, Etiologyhttps://emedicine.medscape.com/article/123447-overview
Multiple endocrine neoplasias type 2 (MEN2) is an inherited disorder characterized by the development of medullary thyroid cancer (MTC), parathyroid tumors, and pheochromocytoma. MEN2 results from germline mutations in the RET proto-oncogene and is transmitted in an autosomal dominant fashion. There are two MEN2 syndromes: MEN2A and MEN2B. […] The overall frequency of MEN2 in the United States is 1 case per 30,000-50,000 population. In decreasing order of frequency, MEN occurs as follows: MEN2A, MEN2A with FMTC only, and MEN 2B. […] In MEN2A patients, 50% of those with RET gene mutations develop disease by age 50 years, and 70% develop the disease by age 70 years. MTC has been detected shortly after birth in MEN2B.
- #4 Multiple Endocrine Neoplasia Type 2 | Children’s Hospital of Philadelphiahttps://www.chop.edu/conditions-diseases/multiple-endocrine-neoplasia-type-2
MEN2 is a hereditary cancer syndrome, affecting approximately 1 in 35,000 people. […] The true prevalence of MEN2 is likely underestimated because the disease may go unrecognized in certain individuals. It is important to identify this hereditary cancer syndrome early, as it often confers a high risk of tumors, which may occur at a younger-than-expected age. […] Most pediatric patients are diagnosed based on a parent or family member having MEN2. […] About 95 percent of people with MEN2A will develop medullary thyroid cancer during their lifetime, but the risk of developing pheochromocytoma and/or hyperparathyroidism range between 10 to 50 percent and depends on the specific RET gene abnormality (codon). […] Children diagnosed with MEN2 will need lifelong follow-up care and cancer screening.
- #5 Orphanet: Multiple endocrine neoplasia type 2https://www.orpha.net/en/disease/detail/653
A rare multiple endocrine neoplasia (MEN) syndrome that is principally characterized by the association of medullary thyroid carcinoma (MTC) with other endocrine tumors. The variant MEN 2A is defined by MTC associated with pheochromocytoma and/or primary hyperparathyroidism (MEN2A); the variant MEN 2B is defined as an aggressive form of MTC in association with pheochromocytoma but without primary hyperparathyroidism. […] The total prevalence of all variants of multiple endocrine neoplasia type 2 (MEN2) is approximately 1/35,000. MEN2A, accounts for 95% of MEN2 cases. […] MEN2 can affect all age groups, with manifestations beginning in infancy to early childhood (MEN2B) or adulthood (MEN2A). […] MEN2 is caused by a heterozygote germline activating mutation in the RET proto-oncogene (10q11.2), encoding a membrane tyrosine kinase receptor.
- #6 Orphanet: Multiple endocrine neoplasia type 2https://www.orpha.net/en/disease/detail/653
MEN2 is an autosomal-dominant syndrome and individuals carrying the pathogenic variant have a 50% risk of transmitting the variant to each offspring, independent of sex. Approximately 75% of MEN2B cases are sporadic (with the RET mutation arising de novo), while 25% are familial. […] RET mutation predicts the clinical phenotype and guides treatment. As recommended by the American thyroid association, management and treatment is stratified according to risk of aggressive MTC: highest risk (HST); high risk (H); moderate risk (MOD). […] The prognosis depends on the stage at which MTC is diagnosed and efficacy of initial surgical treatment. Early diagnosis and complete initial resection of tumors increases life expectancy.
- #7 Multiple Endocrine Neoplasias – MEN | Choose the Right Testhttps://arupconsult.com/content/multiple-endocrine-neoplasias
Multiple endocrine neoplasia (MEN) syndromes are characterized by tumors involving multiple endocrine glands. Subtypes MEN1 and MEN2 are distinguished by clinical features and molecular testing. MEN2 includes the additional subtypes MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC). […] […] MEN2 […] Incidence 1/35,000 […] MEN2A 70-80% of cases […] Familial medullary thyroid carcinoma (FMTC) 10-20% of cases […] MEN2B ~5% of cases. […] […] Autosomal dominant 5% of MEN2A and 50% of MEN2B mutations are de novo. […] Caused by mutation in the RET proto-oncogene refer to ARUP’s MEN2 and RET database. […] Genotype/phenotype correlations can help predict risk for aggressive FMTC. […] Penetrance varies by MEN2 subtype […] MEN2A 95% […] MEN2B and FMTC nearly 100%.
- #8 Incidence and prevalence of multiple endocrine neoplasia 2A in Denmark | CLEPhttps://www.dovepress.com/incidence-and-prevalence-of-multiple-endocrine-neoplasia-2a-in-denmark-peer-reviewed-fulltext-article-CLEP
The incidence and prevalence of multiple endocrine neoplasia 2A (MEN2A) have only been reported once in a nationwide setting. […] We conducted a nationwide retrospective cohort study of MEN2A in Denmark from 1901 to 2014, aiming to describe the incidence and prevalence. […] The incidence from 1971 to 2000 was 28 (95% CI: 2137) per million live births per year. […] Point prevalence at January 1, 2015, was 24 per million (95% CI: 2028). […] The incidence and prevalence of MEN2A in Denmark seem higher than those reported in other countries. This is likely explained by the Danish C611Y founder effect. […] Also, our data indicate no significant change in MEN2A incidence during the last century.
- #9 Multiple Endocrine Neoplasia in Childhood: An Update on Diagnosis, Screening, Management and Treatmenthttps://www.mdpi.com/2673-396X/3/1/7
Multiple endocrine neoplasia (MEN) is a rare group of inherited disorders with the occurrence of two or more endocrine gland tumors in an individual or related individuals in the same family. […] MEN2 is further divided into MEN2A, MEN2B (formerly known MEN3), and familial medullary thyroid carcinoma (FMTC). […] The estimated prevalence of MEN2âincluding MEN2A, MEN2B, FMTC, and other subtypesâis 1 in 30,000. […] While MEN2A and MEN2B are both characterized by medullary thyroid carcinoma (MTC) and pheochromocytoma (PHEO), clinical features and age of onset differ between the two forms. […] In all variants of MEN2, the lifetime risk of developing MTC is nearly 100%. […] For this reason, guidelines recommend that all patients in whom MTC is identified receive routine genetic screening for RET mutations.
- #10 Multiple Endocrine Neoplasia Type 2 – Endocrine Surgery | UCLA Healthhttps://www.uclahealth.org/medical-services/surgery/endocrine-surgery/patient-resources/patient-education/endocrine-surgery-encyclopedia/multiple-endocrine-neoplasia-type-2
Multiple Endocrine Neoplasia II (MEN II) is a hereditary disorder in which a type of thyroid cancer accompanied by recurring cancer of the adrenal glands. […] The cause of MEN II is genetic — a mutation in a gene called RET. Multiple tumors may appear in the same person, but not necessarily at the same time. The adrenal tumor is a pheochromocytoma and the thyroid tumor is a medullary carcinoma of the thyroid. […] The disorder may occur at any age, and affects men and women equally. The main risk factor is a family history of MEN II. […] Diagnosis depends on identification of mutation of the RET gene. This can be done with a blood test. […] Family members should be screened for the RET gene mutation. […] Screening of close relatives of a person with MEN II may lead to early detection.
- #11 Multiple endocrine neoplasia (MEN) II Information | Mount Sinai – New Yorkhttps://www.mountsinai.org/health-library/diseases-conditions/multiple-endocrine-neoplasia-men-ii
Multiple endocrine neoplasia, type II (MEN II) is a disorder passed down through families in which one or more of the endocrine glands are overactive or form a tumor. […] The disorder may occur at any age, and affects men and women equally. The main risk factor is a family history of MEN II. […] Screening close relatives of people with MEN II may lead to early detection of the syndrome and related cancers. This may allow for steps to prevent complications.
- #12 Multiple Endocrine Neoplasia in Childhood: An Update on Diagnosis, Screening, Management and Treatmenthttps://www.mdpi.com/2673-396X/3/1/7
MEN2A, also known as Sipple syndrome, has an estimated prevalence of 1 in 36,000 to 1 in 200,000 live births. […] A diagnosis of MEN2A is made when a child has two or more of the following endocrine manifestations: MTC, PHEO, and/or PHPT. […] MTC is typically the first manifestation of MEN2A and occurs in more than 90% of individuals. […] The peak incidence of MTC in MEN2A patients is in the third decade of life. […] In children, MTC may present before the age of 6, with some cases identified in children as young as 2 years of age. […] PHEO and PHPT more commonly present in adulthood. […] The development of the two tumors is significantly affected by the specific underlying RET gene mutation and mutation penetrance. […] In adults, up to 50% of individuals with MEN2A present with PHEO in the second to third decade of life.
- #13 Multiple Endocrine Neoplasia: Ocular Features – EyeWikihttps://eyewiki.org/Multiple_Endocrine_Neoplasia:_Ocular_Features
Multiple endocrine neoplasia (MEN) syndrome, ICD-10 code: E31.20. […] The prevalence of MEN2 cases is approximately 1 per 35,000. […] The epidemiology of MEN2B is unknown. […] MEN2B is typified by the association of MTC, pheochromocytoma, mucosal neuromas and intestinal ganglioneuromatosis. […] MTC in MEN2B develops earlier and behaves more aggressively than in MEN2A. […] Pheochromocytoma develops in 40%-50% of patients with MEN2B. […] Early preventative surgery includes a total thyroidectomy and central lymph node dissection during the first few months of life in patients with germ-line mutations of codons 883, 918 and 922 in MEN2B. […] This is due to the lifetime penetrance of MTC that is nearly 100% in carriers of these RET mutations. […] Patients with MEN2B develop MTC in the first and second decades of life. […] Lethal outcomes may be prevented by the early diagnosis and treatment of a patient with suspected MEN2B.
- #14 Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2 – UpToDatehttps://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-multiple-endocrine-neoplasia-type-2/print
Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant disorder with an estimated prevalence of 1 per 30,000 in the general population. MEN2 is subclassified into two distinct syndromes: types 2A (MEN2A) and 2B (MEN2B). […] The genetic defect in these disorders involves the RET proto-oncogene on chromosome 10. MEN2A and 2B are inherited in an autosomal dominant pattern with very high penetrance. In both syndromes, there is an occurrence of multicentric tumor formation in all organs where the RET proto-oncogene is expressed. The thyroid, parathyroid, and adrenal glands are at risk for developing tumors that may reduce life expectancy and quality of life. The excellent prognosis for medullary thyroid cancer (MTC) diagnosed at its earliest stage underscores the importance of early diagnosis for sporadic and hereditary MTC. […] This topic will review the clinical manifestations, diagnosis, and evaluation of MEN2.
- #15 Multiple endocrine neoplasia type 2 — Knowledge Hubhttps://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/multiple-endocrine-neoplasia-type-2/
MEN2 is inherited in an autosomal dominant pattern. The child of an individual with MEN2 has a 50% chance of inheriting the pathogenic RET variant. The type of clinical surveillance, the age of testing and the age at which a prophylactic thyroidectomy should be offered to proven carriers all vary depending on the risk category of the RET variant. […] Management of MTC, phaeochromocytoma or primary hyperparathyroidism in patients with MEN2 should be led by a specialist multidisciplinary team. Patients with MEN2 should be offered surveillance for phaeochromocytoma and primary hyperparathyroidism as per their RET gene risk.
- #16 Multiple endocrine neoplasia, type 2 (MEN 2) | UM Health-Sparrowhttps://www.uofmhealthsparrow.org/departments-conditions/conditions/multiple-endocrine-neoplasia-type-2-men-2
Multiple endocrine neoplasia, type 2, also called MEN 2, is a rare condition. It causes tumors in the thyroid and parathyroid glands, adrenal glands, lips, mouth, eyes and digestive tract. Genetic testing can find the changed gene that causes MEN 2. Health care providers can treat the health issues that gene may cause. […] MEN 2 is an inherited disorder. This means people who have the changed gene can pass it on to their children. Each child has a 50% chance of getting the disorder. […] Many people also may be the first person in their families to have this disorder. People diagnosed with medullary thyroid cancer are screened regularly for MEN 2. […] Genetic testing is used to find out if someone has a changed gene that causes MEN 2. Children of someone who has this changed gene could inherit it and develop MEN 2. Parents and siblings also could have the changed gene even if they don’t have symptoms.
- #16 Multiple endocrine neoplasia, type 2 (MEN 2) | UM Health-Sparrowhttps://www.uofmhealthsparrow.org/departments-conditions/conditions/multiple-endocrine-neoplasia-type-2-men-2
If someone in your family is diagnosed with MEN 2, your health care provider will likely recommend you and your family members have genetic testing. This is because MEN 2 can be treated or managed by removing the thyroid gland early in life. Being screened for parathyroid or adrenal tumors also can help. […] If no gene changes are found in family members, usually no other screening tests are needed. However, genetic testing doesn’t find all MEN 2 gene changes. If MEN 2 isn’t found in people who may have it, they and their family members will have regular blood and imaging tests over time to check for signs of the disease.
- #17 Multiple Endocrine Neoplasia Type 2 (MEN2) (PDQ®) – NCIhttps://www.cancer.gov/publications/pdq/information-summaries/genetics/men2-hp-pdq
MEN2 is caused by pathogenic variants in the RET gene. […] The prevalence of MEN2 has been estimated to be approximately 1 in 35,000 individuals. […] The understanding of MEN2’s natural history continues to evolve. […] Genetic testing is an important management tool that defines who has an MEN2 diagnosis. […] Germline DNA testing for RET pathogenic variants is recommended for all individuals with medullary thyroid cancer (MTC) by the American Thyroid Association and the National Comprehensive Cancer Network. […] The ATA recommends that annual screening for PHEO be considered by age 11 years in patients with ATA-HST or ATA-H RET pathogenic variants. […] The ATA provides recommendations for annual screening for hyperparathyroidism, with screening beginning by age 11 years in carriers of ATA-HST and ATA-H pathogenic variants and by age 16 years for carriers of ATA-MOD RET pathogenic variants.
- #18 Multiple endocrine neoplasia type 2 | Orphanet Journal of Rare Diseases | Full Texthttps://ojrd.biomedcentral.com/articles/10.1186/1750-1172-1-45
Multiple Endocrine Neoplasia Type 2 (MEN2) is a rare hereditary complex disorder characterized by the presence of medullary thyroid carcinoma (MTC), unilateral or bilateral pheochromocytoma (PHEO) and other hyperplasia and/or neoplasia of different endocrine tissues within a single patient. MEN2 has been reported in approximately 500 to 1000 families worldwide and the prevalence has been estimated at approximately 1:30,000. […] Currently, DNA testing makes possible the early detection of asymptomatic gene carriers, allowing to identify and treat the neoplastic lesions at an earlier stage. […] At present, surgical treatment offers the only chance of cure and therefore, early clinical and genetic detection and prophylactic surgery in subjects at risk are the main therapeutic goal.
- #19 RET (MEN2) â risk managementhttps://www.eviq.org.au/cancer-genetics/adult/risk-management/1526-ret-men2-risk-management
In patients with MEN2B the risk of primary hyperparathyroidism is no higher than that of the general population and surveillance is not required. […] First degree blood relatives (parents/brothers/sisters/children) are at up to 50% risk of having inherited the pathogenic variant. More distant relatives may also be at risk of inheriting the pathogenic variant. […] RET pathogenic variant carriers of childbearing age should be offered genetic counselling, including the options of pre-implantation genetic diagnosis and prenatal testing.
- #20 Multiple Endocrine Neoplasia Type 2 and the RET gene – Sydney Cancer Geneticshttps://www.sydneycancergenetics.com.au/genes-and-syndromes/multiple-endocrine-neoplasia-type-2-and-the-ret-gene/
Multiple Endocrine Neoplasia syndrome Type 2 is rare, affecting 1 in 30,000 people. It is caused by a mutation in the RET gene. […] Screening for medullary thyroid cancer is not effective. Fortunately, surgery, called thyroidectomy, is preventative. Thyroidectomy is recommended by age 5 if it is a high risk mutation (as classified by the American Thyroid Association) and usually by age 10. The timing depends on the location of the mutation in the RET gene. […] Thyroidectomy is strongly recommended in first months of life for MEN2B, usually as soon as the baby is fit for surgery. […] Yes. Multiple Endocrine Neoplasia syndrome type 2 is a hereditary cancer syndrome. There is a 50% chance of a person who carries a germline RET mutation, whether male or female, passing the mutation to their son or daughter. If a mutation is identified, then predictive testing is available for blood relatives. This testing is Medicare funded.
- #21 Multiple Endocrine Neoplasia (MEN) Type 2 | American Thyroid Associationhttps://www.thyroid.org/multiple-endocrine-neoplasia-men-type-2/
MEN 2 (Multiple Endocrine Neoplasia Syndrome type 2) is a group of diseases including a type of thyroid cancer called Medullary Thyroid Cancer (MTC). […] If you are diagnosed with either form of MEN2, you will need life-long monitoring by an endocrinologist. […] In MEN 2, PHEO is usually a benign tumor and not cancer.
- #22 Multiple Endocrine Neoplasia Type 2 (MEN2) Guidelines: Guidelines Summary, Pheochromocytoma, Parathyroid Diseasehttps://emedicine.medscape.com/article/123447-guidelines
Predictive RET gene testing is the clinical standard of care for all individuals with a positive family history of MEN2 because of the very high risk of early-onset MTC in affected individuals, including children. […] The ATA guidelines recommend screening for pheochromocytoma by measuring free plasma metanephrines and normetanephrines or 24-hour urinary metanephrines and normetanephrines. Adrenal imaging with CT or MRI is indicated in patients with positive biochemical results. The following patients should be screened: children in the high risk (ATA-H) and highest risk (ATA-HST) categories by age 11 years, children in the moderate risk (ATA-MOD) category by age 16, women with MEN2 who are planning a pregnancy or are pregnant; if detected, pheochromocytoma should be treated prior to the third trimester.
- #22 Multiple Endocrine Neoplasia Type 2 (MEN2) Guidelines: Guidelines Summary, Pheochromocytoma, Parathyroid Diseasehttps://emedicine.medscape.com/article/123447-guidelines
In 2015, the American Thyroid Association (ATA) published revised guidelines for the diagnosis and treatment of medullary thyroid carcinoma (MTC) that included recommendations for management of multiple endocrine neoplasia type 2 (MEN2). The National Comprehensive Cancer Network (NCCN) includes recommendations for diagnosis and treatment of MEN2 in its guidelines for thyroid cancer and its guideline for neuroendocrine and adrenal tumors. […] According to NCCN guidelines, the criterion for a clinical diagnosis of MEN2A is two or more MEN2A-associated tumors (medullary thyroid carcinoma [MTC], adrenal pheochromocytoma) in an individual or in a first-degree relative. Other physical findings include lichen planus amyloidosis and Hirschsprung disease. […] NCCN guidelines recommend offering a MEN2 clinical evaluation to individuals with a clinical diagnosis or suspicion of MEN2, even those with a negative RET genetic test. At-risk relatives should also be offered evaluation even if RET mutation has not been identified or if RET genetic testing has not been performed in the affected family member. Clinical evaluation should include the following tests: biochemical tests of hormone levels, imaging tests to localize MEN2-associated tumors, genetic counseling and testing.
- #23 Multiple Endocrine Neoplasia Type 2 | St. Jude Care & Treatmenthttps://www.stjude.org/care-treatment/treatment/genetic-syndromes/multiple-endocrine-neoplasia-type-2.html
It is recommended that children with MEN2 have surgery to remove their thyroid. […] Recommended screenings for people with MEN2 include: Yearly physical exams by a health care provider who is familiar with MEN2, Yearly neck ultrasound and serum calcitonin (blood test) starting in the first few months of life to ages 35 years, depending on the RET mutation.
- #24 Multiple Endocrine Neoplasia Type 2 (MEN2) (PDQ®): Genetics – Health Professional Information [NCI] – Family Health Associateshttps://fhahermiston.com/patient-education/healthwise?DOCHWID=ncicdr0000813377
MEN2 is caused by pathogenic variants in the RET gene. The prevalence of MEN2 has been estimated to be approximately 1 in 35,000 individuals. The understanding of MEN2’s natural history continues to evolve. Clinical observations suggest that the natural history of MEN2 (particularly the penetrance of MTC) is variable. Current stratification has moved away from a solely phenotype-based classification to one that is based on genotype (i.e., the pathogenic variant) and phenotype. The ATA recommends that annual screening for PHEO be considered by age 11 years in patients with ATA-HST or ATA-H RET pathogenic variants. The ATA recommends that patients with ATA-Moderate Risk (MOD) RET pathologic variants have periodic screening for PHEO beginning by age 16 years. Primary hyperparathyroidism is variably reported in MEN2A, with rates ranging from 2% to 35%. The ATA provides recommendations for annual screening for hyperparathyroidism, with screening beginning by age 11 years in carriers of ATA-HST and ATA-H pathogenic variants and by age 16 years for carriers of ATA-MOD RET pathogenic variants.
- #25 Multiple endocrine neoplasia type 2: An overview | Genetics in Medicinehttps://www.nature.com/articles/gim2011127
Approximately 50% of individuals diagnosed with MTC who have undergone total thyroidectomy and neck nodal dissections have recurrent disease. […] Therefore, continued monitoring for residual or recurrent MTC is indicated after thyroidectomy, even if thyroidectomy is performed before biochemical evidence of disease.
- #25 Multiple endocrine neoplasia type 2: An overview | Genetics in Medicinehttps://www.nature.com/articles/gim2011127
MEN 2A makes up approximately 70-80% of cases of MEN 2. As genetic testing for RET mutations has become available, it has become apparent that 70-95% of individuals with MEN 2A develop MTC, approximately 50% develop pheochromocytoma, and approximately 15-30% develop HPT. […] MEN 2B is characterized by the early development of an aggressive form of MTC in all affected individuals. […] Prophylactic thyroidectomy is the primary preventive measure for individuals with an identified germline RET mutation. […] For all individuals with a RET mutation who have not had a thyroidectomy, annual biochemical screening is recommended with immediate thyroidectomy if results are abnormal. […] Annual biochemical screening beginning at age 8 years has been recommended for individuals with MEN 2A or FMTC caused by mutations of codons 630 and 634 and at age 20 years for mutations in all other codons.
- #26 Multiple Endocrine Neoplasia Type 2 (MEN2) Guidelines: Guidelines Summary, Pheochromocytoma, Parathyroid Diseasehttps://emedicine.medscape.com/article/123447-guidelines
Surveillance intervals for patients with pheochromocytomas following a complete resection include the following: history, physical examination with blood pressure, and tumor markers measured after 3 to 12 months, then every 6 months for the first 3 years and annually for up to 10 years. Chest CT with or without contrast, abdominal/pelvic CT or MRI with contrast, or FDG-PET/CT can be considered.
- #27 Multiple Endocrine Neoplasia | MD Anderson Cancer Centerhttps://www.mdanderson.org/cancer-types/multiple-endocrine-neoplasia.html
Multiple endocrine neoplasia type 2 (MEN2) is divided into three types: MEN2A, MEN2B, and Familial Medullary Thyroid Carcinoma (FMTC). […] People with multiple endocrine neoplasia type 2 (MEN2) have a 95% chance of developing medullary thyroid cancer. […] Genetic testing of blood samples can confirm a diagnosis of MEN2 and identify family members at risk of developing the disease. […] General recommendations are to remove the thyroid gland: Within the first six months of life for individuals with MEN2B; By five to 10 years of age for individuals with MEN2A and FMTC. […] Pheochromocytoma is diagnosed in about 50% of people with MEN2A and MEN2B, although they do not occur in true FMTC. […] If detected early, pheochromocytomas are easily treated. However, if not treated, they may be potentially fatal due to dangerously high blood pressures that can occur during accidents, surgery, childbirth or other physically stressful situations.
- #28 Multiple endocrine neoplasia type 2A | Endocrine Conditionshttps://www.yourhormones.info/endocrine-conditions/multiple-endocrine-neoplasia-type-2a/
Multiple endocrine neoplasia type 2 (MEN2) is a rare inherited disorder in which medullary thyroid cancer, phaeochromocytoma and overactive parathyroid glands develop. […] MEN2A is a rare condition occurring in approximately 1 in 25,000 people. […] MEN2A is an inherited condition due to an abnormality or spelling mistake (mutation) in the RET gene, which can be passed on from parent to child. It is inherited in an 'autosomal dominant’ way. […] If a patient is found to have MEN2A, lifelong surveillance is recommended. Patients should be cared for in a specialist centre under the guidance of an experienced multidisciplinary team. Screening is performed for the conditions listed above with a combination of blood tests and scans as appropriate.
- #29https://www.singhealth.com.sg/patient-care/conditions-treatments/multiple-endocrine-neoplasia-type-2
Genetic testing can confirm the correct genetic diagnosis and help guide surveillance and medical management based on the risks associated with the particular condition. […] Surveillance can help detect tumours and cancer at an early and manageable stage, and avoid irreversible or serious medical complications.
- #30 Multiple Endocrine Neoplasia in Childhood: An Update on Diagnosis, Screening, Management and Treatmenthttps://www.mdpi.com/2673-396X/3/1/7
Children born to parents with MEN2B should obtain genetic testing for RET mutations. […] In cases where there is resistance to parental disclosure and child testing, legal intervention may be necessary as the child is at great risk for inheriting a malignant tumor. […] Given that all children with MEN2B will develop MTC and particular RET codons may present with more aggressive MTC in children with MEN2A, screening and diagnosis is imperative in the prevention of metastatic MTC at an early age. […] Individuals diagnosed with MEN2 are recommended to be screened annually for the presence of PHEO and PHPT even if asymptomatic.
- #31 Advances in risk-oriented surgery for multiple endocrine neoplasia type 2 in: Endocrine-Related Cancer Volume 25 Issue 2 (2018)https://erc.bioscientifica.com/view/journals/erc/25/2/ERC-17-0202.xml
Genetic association studies hinge on definite clinical case definitions of the disease of interest. This is why more penetrant mutations were overrepresented in early multiple endocrine neoplasia type 2 (MEN2) studies, whereas less penetrant mutations went underrepresented. […] The insight into the natural course of the disease gleaned over the past 25 years caused a paradigm shift in MEN2: from the removal of target organs at the expense of greater operative morbidity to close biochemical surveillance and targeted resection of adrenal tumors and hyperplastic parathyroid glands. […] Future research should delineate further the mutation-specific, age-dependent penetrance of pheochromocytoma and primary hyperparathyroidism to refine the risk-oriented approach to MEN2. […] The sweeping changes in the management of MEN2 since the new millenium hold the hope that death and major morbidity from this uncommon disease can be eliminated in our lifetime.