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Multiple Endocrine Neoplasia Type 2B

MEN2B

Multiple endocrine neoplasia type 2B is a rare disorder in which aggressive medullary thyroid cancer, pheochromocytoma may lead to life-threatening blood pressure changes, and mucosal neuromas are included in the clinical presentation. The majority of patients develop symptoms by the first few years of age. Through laboratory, imaging, and genetic studies, the diagnosis must be made early on in order to prevent complications.


Presentation

Two multiple endocrine neoplasia (MEN) syndromes are described in the literature - MEN 1 and MEN 2, and multiple endocrine neoplasia type 2B, is one of the subtypes of MEN 2, presenting with several distinguishing features [1] [2] [3] [4] [5]:

  • Medullary thyroid cancer (MTC) - Virtually all patients who suffer from MEN type 2B develop an aggressive MTC that appears during the first several months of life, which is why total thyroidectomy is often indicated, both as a prophylactic and as a therapeutic measure [5] [6] [7]. Main complaints related to MTC are localized pain in the neck, often accompanied by a palpable mass [3] [8].
  • Pheochromocytoma - In approximately 50% of cases, tumors of the adrenal gland (either unilateral or bilateral) are recorded and cause blood pressure changes due to the ongoing production of catecholamines (norepinephrine and epinephrine) [3] [4] [6] [9].
  • Mucosal neuromas - Defined as one of the crucial clinical features of MEN type 2B, these lesions appear in the oral cavity (the anterior dorsal surface of the tongue, the pharynx, the buccal surfaces, and the palate) in infancy and childhood [3] [6] [8] [10]. Neuromas might appear on the eyelids (causing eversion of the upper eyelid and thickening) and the lips, giving them a "blueberry" color [3].

In addition, other prominent findings are gastrointestinal complaints (feeding difficulties, vomiting, dysphagia, abdominal pain, and either constipation or diarrhea, presumably arising from excessive calcitonin secretion due to MTC), musculoskeletal changes (kyphosis, hip dislocation, a Marfanoid appearance, as well as flat foot and pes cavus), and a flat facies with hypertelorism [3] [6] [10]

Marfanoid Habitus
  • From Wikidata Jump to navigation Jump to search autosomal dominant disease characterized by medullary thyroid carcinoma, pheochromocytoma, multiple mucosal neuromas and intestinal ganglioneuromas, and often a marfanoid habitus and other skeletal abnormalities[wikidata.org]
  • A sporadic case of multiple endocrine neoplasia type 2B in a twenty-six year old man who manifested medullary thyroid carcinoma, multiple mucosal neuromas of the tongue and a marfanoid habitus is reported.[ncbi.nlm.nih.gov]
Fatigue
  • However, most people with endocrine disease complain of fatigue and weakness. Blood and urine tests to check your hormone levels can help your doctors determine if you have an endocrine disorder.[webmd.com]
  • Hypercalcaemia may lead to constipation, polyuria, polydipsia, memory problems, depression, nephrolithiasis, glucose intolerance, gastro-oesophageal reflux and fatigue.[patient.info]
  • Nuclear medicine treatments may cause fatigue and may affect the bone marrow causing anaemia and low platelet count, which can result in bleeding problems, and a low white cell count, which can result in increase risk of infections.[yourhormones.info]
  • […] skipped heartbeats) Feelings of anxiety or feelings of extreme fright Pain in the lower chest or upper abdomen Nausea with or without vomiting Weight loss Pale skin Feeling hot or unable to tolerate being in the heat Hyperparathyroidism signs and symptoms Fatigue[stjude.org]
Hypoxemia
  • Intubation and mechanical ventilation were performed because of severe hypoxemia.[ncbi.nlm.nih.gov]
Localized Pain
  • Main complaints related to MTC are localized pain in the neck, often accompanied by a palpable mass.[symptoma.com]
Turkish
  • We report the case of a 19-year-old Turkish girl who presented with skin-colored flat papules scattered all over the trunk and extremities.[ncbi.nlm.nih.gov]
Mediastinal Disease
  • disease by magnetic resonance imaging, proved that the metastases were from his previous adrenal and not thyroid tumor.[ncbi.nlm.nih.gov]
Abdominal Pain
  • The alimentary tract manifestations were diverse: symptoms included constipation, diarrhea, difficulty with feeding, projectile vomiting, crampy abdominal pain, and loud borborygmi; findings included thickened lips, nodules on the anterior third of the[ncbi.nlm.nih.gov]
  • In addition, other prominent findings are gastrointestinal complaints (feeding difficulties, vomiting, dysphagia, abdominal pain, and either constipation or diarrhea, presumably arising from excessive calcitonin secretion due to MTC), musculoskeletal[symptoma.com]
  • Gastrointestinal symptoms such as FTT, abdominal pain, dysphagia, projectile vomiting, diarrhea, constipation, flatulence, intussusceptions, megacolon, and pseudo obstruction are considered as possible manifestations of MEN2B [ 9 ].[jmedicalcasereports.biomedcentral.com]
Nausea
  • […] and symptoms Fatigue or weakness Feeling depressed Forgetfulness Bone and joint pain Complaining often of illness with no known cause Fragile bones that easily break (osteoporosis) Kidney stones Increased thirst and urinating too often Pain in abdomen Nausea[stjude.org]
  • Adverse events included diarrhea, rash, nausea, hypertension, and headache ( 22 ).[clincancerres.aacrjournals.org]
  • Hyperparathyroidism disrupts the normal balance of calcium in the blood, which can lead to kidney stones, thinning of bones, nausea and vomiting, high blood pressure (hypertension), weakness, and fatigue.[endocrine.surgery.ucsf.edu]
  • Hyperparathyroidism can cause additional symptoms in some cases including fatigue, weakness, constipation, nausea, ulcers, indigestion, high blood pressure (hypertension), and muscle or bone pain.[rarediseases.org]
Projectile Vomiting
  • The alimentary tract manifestations were diverse: symptoms included constipation, diarrhea, difficulty with feeding, projectile vomiting, crampy abdominal pain, and loud borborygmi; findings included thickened lips, nodules on the anterior third of the[ncbi.nlm.nih.gov]
  • Keywords Medullary Thyroid Carcinoma Neuroma Medullary Thyroid Cancer Prophylactic Thyroidectomy Projectile Vomiting Introduction Multiple endocrine neoplasia 2B (MEN2B) is a rare autosomal dominant syndrome [ 1 – 4 ].[jmedicalcasereports.biomedcentral.com]
Progressive Dysphagia
  • Her late clinical course was dominated by progressive dysphagia, intestinal dysmotility and megacolon associated with unrelenting malnutrition.[ncbi.nlm.nih.gov]
Borborygmi
  • The alimentary tract manifestations were diverse: symptoms included constipation, diarrhea, difficulty with feeding, projectile vomiting, crampy abdominal pain, and loud borborygmi; findings included thickened lips, nodules on the anterior third of the[ncbi.nlm.nih.gov]
Macroglossia
  • Between ages 2 and 4, they develop full lips, large rounded cheeks , a broad nose , and an enlarged tongue ( macroglossia ). The vocal cords also enlarge, which results in a deep, hoarse voice.[ghr.nlm.nih.gov]
Dry Eyes
  • eyes or lack of tears, which is an especially helpful sign in children; delayed puberty.[en.wikipedia.org]
Conjunctival Hyperemia
  • Clinical examination revealed a marfanoid habitus, myelinated corneal nerve fibers, neuromas in the perilimbal area, conjunctival hyperemia with peripheral corneal neovascularization, and posterior blepharitis.[ncbi.nlm.nih.gov]
  • A 16-year-old girl was admitted with severe bilateral conjunctival hyperemia and stinging lasting for more than 1 year.[healio.com]
Blepharitis
  • Clinical examination revealed a marfanoid habitus, myelinated corneal nerve fibers, neuromas in the perilimbal area, conjunctival hyperemia with peripheral corneal neovascularization, and posterior blepharitis.[ncbi.nlm.nih.gov]
Long Arm
  • Multipoint analysis of RFLPs at FNRB, D10Z1, RBP3, and D10S15 gave a peak lod score of 7.12 at the midpoint between D10Z1 and RBP3 on the long arm (band q11).[ncbi.nlm.nih.gov]
  • People with MEN2B typically have a body type with long arms, legs, and fingers.[rarediseases.info.nih.gov]
Hip Dislocation
  • dislocation, a Marfanoid appearance, as well as flat foot and pes cavus), and a flat facies with hypertelorism The diagnosis of MEN type 2B rests on the ability of the physician to recognize the main signs and symptom that will raise clinical suspicion[symptoma.com]
Self-Mutilation
  • Oro-dental features include a lack of tongue fungiform papillae, impairment of taste, oro-dental self-mutilation, dental crowding, excessive plaque and calculus accumulation, salivary over production and low caries experience.[ncbi.nlm.nih.gov]
Self Mutilation
  • Oro-dental features include a lack of tongue fungiform papillae, impairment of taste, oro-dental self-mutilation, dental crowding, excessive plaque and calculus accumulation, salivary over production and low caries experience.[ncbi.nlm.nih.gov]
Hypertelorism
  • […] abdominal pain, and either constipation or diarrhea, presumably arising from excessive calcitonin secretion due to MTC), musculoskeletal changes (kyphosis, hip dislocation, a Marfanoid appearance, as well as flat foot and pes cavus), and a flat facies with hypertelorism[symptoma.com]
Absent Deep Tendon Reflex
  • The typical clinical features consist of somatic abnormalities: failure to thrive, characteristic facies, excessive sweating, labile blood pressure, recurrent aspiration pneumonias, lack of tears, and diminished and later absent deep tendon reflexes with[ncbi.nlm.nih.gov]

Workup

The diagnosis of MEN type 2B rests on the ability of the physician to recognize the main signs and symptom that will raise clinical suspicion. Firstly, a detailed patient history and a thorough physical examination should be performed, during which mucosal neuromas must be identified. Although MEN syndromes exhibit an autosomal dominant pattern of inheritance (meaning that a family history can be crucial for making the diagnosis), many patients develop de novo mutations of the RET proto-oncogene, the main event in the pathogenesis of multiple endocrine neoplasia type 2B [5] [9]. As soon as clinical evidence is obtained, laboratory and imaging studies need to be performed. Serum levels of calcitonin and metanephrines (although urine can be a viable sample for the latter) are useful initial methods to suspect toward MTC and pheochromocytoma, respectively [4] [5] [10]. Computed tomography (CT) and magnetic resonance imaging (MRI) are recommended for internal organ evaluation and confirmation of the two tumors in the patients, whereas barium enema and other radiographic studies of the gastrointestinal tract commonly may reveal a megacolon and dilation of the small bowel [3] [4] [10]. MTC should be further solidified by performing a biopsy with subsequent histopathological examination and immunohistochemistry [3].

Liver Biopsy
  • In 1975, angiography revealed extensive hepatic lesions metastatic from the medullary thyroid carcinoma; this finding was confirmed by open liver biopsy in 1988.[ncbi.nlm.nih.gov]
  • Liver biopsy showed that hepatic lesions were immunohisto-chemically positive for calcitonin and CEA.[academic.oup.com]

Treatment

  • Family screening is essential to identify at-risk family members for prophylactic treatment.[ncbi.nlm.nih.gov]

Prognosis

  • Since multiple endocrine neoplasia type 2B has a relatively poor prognosis because of the occasional aggressive behavior of medullary thyroid carcinoma, the necessity of the genetic diagnosis of multiple endocrine neoplasia in the early stage is suggested[ncbi.nlm.nih.gov]

Etiology

  • A specific missense mutation in the RET proto-oncogene is the etiology of multiple endocrine neoplasia type B, in contrast to very complex multigenetic defects that underlie Hirschsprung's disease, which include overt mutations and more subtle changes[ncbi.nlm.nih.gov]
  • DISCUSSION Etiology/epidemiology Multiple endocrine neoplasia (MEN) is an autosomal dominant syndrome that results in the predisposition to tumor formation in two or more endocrine glands.[webeye.ophth.uiowa.edu]
  • (Etiology) MEN 2 Syndrome is caused by the mutation in the RET proto-oncogene on the chromosome 10; the proto-oncogene stimulates the proliferation of cancer cells.[dovemed.com]
  • Etiology Point mutations associated with MEN2A and the FMTC-only subtype have been identified in exons 10 and 11. Evidence of genotype/phenotype correlation exists.[emedicine.medscape.com]
  • Knudson, Genetics and Etiology of Human Cancer, Advances in Human Genetics 8, 10.1007/978-1-4615-8267-0_1, (1-66), (1977).[doi.org]

Epidemiology

  • DISCUSSION Etiology/epidemiology Multiple endocrine neoplasia (MEN) is an autosomal dominant syndrome that results in the predisposition to tumor formation in two or more endocrine glands.[webeye.ophth.uiowa.edu]
  • PubMed CrossRef Google Scholar NCI (2005) Surveillance, epidemiology and end results. Vol. 2005.[springerlink.com]
  • However, none ever gained sufficient traction to merit continued use, and are no longer used in the medical literature. [7] The prevalence of MEN2B is not well established, but has been derived from other epidemiological considerations as 1 in 600,000[en.wikipedia.org]
Sex distribution
Age distribution

Pathophysiology

  • In addition, this article describes the workup, diagnosis, and treatment, along with a discussion of the pathophysiology of MEN 2b as it relates to the dental rehabilitation of a patient with the disorder.[ncbi.nlm.nih.gov]
  • Baron, Neurological features of Fabry disease: clinical, pathophysiological aspects and therapy, Acta Neurologica Scandinavica, 126, 2, (77-97), (2012). Ana M.[doi.org]
  • Pathophysiology MEN2B is secondary to a germline mutation in the RET proto-oncogene on chromosome 10q11. The most common mutation (95%) is M918T in exon 16 and second most common mutation (2-3%) is A883F in exon 15 [3].[webeye.ophth.uiowa.edu]
  • Early total thyroidectomy remains effective in preventing the development of MTC in the long term. [3, 4, 5] Pathophysiology Mutations in RET, a transmembrane proto-oncogene, have been localized to 10q11.2 and are responsible for MEN 2.[emedicine.medscape.com]

Prevention

  • To identify external ophthalmic abnormalities in multiple endocrine neoplasia type 2B (MEN2B), which may facilitate early detection and prophylactic thyroidectomy to prevent medullary thyroid carcinoma.[ncbi.nlm.nih.gov]
  • Clinical recognition and accurate diagnosis of individuals and families who are at risk of harboring a germline RET mutation is critical for the prevention and management of potentially life-threatening neoplasms.[doi.org]
  • Through laboratory, imaging, and genetic studies, the diagnosis must be made early on in order to prevent complications.[symptoma.com]

References

Article

  1. Lee MJ, Chung KH, Park JS, Chung H, Jang HC, Kim JW. Multiple Endocrine Neoplasia Type 2B: Early Diagnosis by Multiple Mucosal Neuroma and Its DNA Analysis. Ann Dermatol. 2010;22(4):452-455.
  2. Kouvaraki MA, Shapiro SE, Perrier ND, Cote GJ, Gagel RF, Hoff AO, et al. RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid. 2005;15:531–544.
  3. Marquard J, Eng C. Multiple Endocrine Neoplasia Type 2. 1999 Sep 27 [Updated 2015 Jun 25]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
  4. Ilias I, Pacak K. Diagnosis, localization and treatment of pheochromocytoma in MEN 2 syndrome. Endocr Regul. 2009;43:89–93.
  5. Znaczko A, Donnelly DE, Morrison PJ. Epidemiology, Clinical Features, and Genetics of Multiple Endocrine Neoplasia Type 2B in a Complete Population. Oncologist. 2014;19(12):1284-1286.
  6. Morrison PJ, Nevin NC. Multiple endocrine neoplasia type 2B (mucosal neuroma syndrome, Wagenmann-Froboese syndrome). J Med Genet. 1996;33:779–782
  7. Morrison PJ, Atkinson AB. Genetic aspects of familial thyroid cancer. The Oncologist. 2009;14:571–577.
  8. Millar S, Bradley L, Donnelly DE, et al. Familial pediatric endocrine tumors. The Oncologist. 2011;16:1388–1396.
  9. Cohen MS, Phay JE, Albinson C, et al. Gastrointestinal Manifestations of Multiple Endocrine Neoplasia Type 2. Annals of Surgery. 2002;235(5):648-655.
  10. Qualia CM, Brown MR, Ryan CK, Rossi TM. Oral Mucosal Neuromas Leading to the Diagnosis of Multiple Endocrine Neoplasia Type 2B in a Child With Intestinal Pseudo-obstruction. Gastroenterol Hepatol (N Y). 2007;3(3):208-211.

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Last updated: 2019-07-11 20:00