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]

  Patients almost always have a marfanoid habitus. [msdmanuals.com]

• 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]

  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]

  Prolactinoma: secretion of milk in women who are not nursing, headaches, sweating, fatigue, weight gain, fertility problems in men and women, and visual problems. [encyclopedia.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]

• 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]

• 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]

  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]

  Adverse events included diarrhea, rash, nausea, hypertension, and headache ( 22 ). [clincancerres.aacrjournals.org]

  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]

• Progressive Dysphagia

  Her late clinical course was dominated by progressive dysphagia, intestinal dysmotility and megacolon associated with unrelenting malnutrition. [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

  (discussed below); low muscle mass, sometimes with myopathy; gastrointestinal complaints, especially constipation; symptoms derived from medullary carcinoma of the thyroid ; symptoms derived from pheochromocytoma ; craniosynostosis ; dry eyes or lack [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 utilizing additional results in three generations of a 15th family have disclosed a peak total lod score of 8.89 at the midpoint between the centromere markers D10Z1 and RBP3 on the long arm (band q11). [ncbi.nlm.nih.gov]

  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). [deepblue.lib.umich.edu]

  These growths can cause signs and symptoms including diarrhea or constipation and may present as early as infancy. [4] People with MEN2B are often tall and may have long fingers, toes, arms, and legs (marfanoid habitus). [rarediseases.info.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]

• 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]

• Protruding Lips

  Our patient presented with multiple keloids, thickened protruding lips, and multiple neuromas of her tongue. [ispub.com]

  […] and tongue Distinctive facial features, including an elongated face and protruding lips A tall and slender body type Medullated corneal nerve fibers (abnormal nerves in the clear covering of the eyeball, which an ophthalmologist can see during an eye [stjude.org]

• 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]

• Mandibular Prognathism

  On physical examination, his face was symmetric and there was no sign of high arched palate, mandibular prognathism, and flat nasal bridge. [jmedicalcasereports.biomedcentral.com]

• Absent Deep Tendon Reflexes

  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]

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].

• Colonic Stricture

  At the age of 29, she developed acute large bowel obstruction requiring sigmoid colectomy; histological examination revealed a benign sigmoid colonic stricture and diverticular disease. [endocrine-abstracts.org]

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

Treatment The main aim of treatment for patients with MEN2B is to increase quantity and quality of life for affected individuals. [news-medical.net]

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]

Further research is needed to improve this prognosis. [news-medical.net]

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]

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]

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]

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]

Audience : National ISSN : 0370-629X e-ISSN : 2566-1566 City : Liège Country : Belgique Keywords : [en] Adrenal Gland Neoplasms/pathology ; Adult ; Ganglioneuroma/pathology ; Humans ; Hyperparathyroidism/pathology ; Multiple Endocrine Neoplasia/diagnosis/epidemiology [orbi.uliege.be]

PubMed CrossRef Google Scholar NCI (2005) Surveillance, epidemiology and end results. Vol. 2005. [springerlink.com]

The most common location is the sternal region, and keloids can also occur on the neck, ears, trunk, and extremities. 3 Epidemiologic data on keloids is limited, but suggests differences among racial groups, with higher rates in African-Americans, Hispanics [ispub.com]

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]

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]

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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.
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