Multiple endocrine neoplasia type 2B

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Multiple endocrine neoplasia type 2b
Other namesMEN 2B, Mucosal neuromata with endocrine tumors, Multiple endocrine neoplasia type 3 ,Wagenmann–Froboese syndrome [1]
Medullary thyroid carcinoma - 2 - very high mag.jpg
Micrograph of medullary thyroid carcinoma, as may be seen in MEN 2b. H&E stain.
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Multiple endocrine neoplasia type 2B (MEN 2B) is a genetic disease that causes multiple tumors on the mouth, eyes, and endocrine glands. It is the most severe type of multiple endocrine neoplasia, [2] differentiated by the presence of benign oral and submucosal tumors in addition to endocrine malignancies. It was first described by Wagenmann in 1922, [3] and was first recognized as a syndrome in 1965-1966 by E.D. Williams and D.J. Pollock. [4] [5] It is caused by the pathogenic variant p.Met918Thr in the RET gene. This variant can cause medullary thyroid cancer and Pheochromocytoma. Presentation can include a Marfanoid body, enlarged lips, and ganglionueuromas.

Contents

MEN 2B typically manifests before a child is 10 years old. Affected individuals tend to be tall and lanky, with an elongated face and protruding, blubbery lips. Benign tumors (neoplasms) develop in the mouth, eyes, and submucosa of almost all organs in the first decade of life. [6] Medullary thyroid cancer almost always occurs, sometimes in infancy. It is often aggressive. Cancer of the adrenal glands (pheochromocytoma) occurs in 50% of cases.

A variety of eponyms have been proposed for MEN 2B, such as Williams-Pollock syndrome, Gorlin-Vickers syndrome, and Wagenmann-Froboese syndrome. However, none ever gained sufficient traction to merit continued use, and they 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 [8] to 1 in 4,000,000. [9] The annual incidence has been estimated at 4 per 100 million per year. [10]

Signs and symptoms

The most common clinical features of MEN2B are:[ citation needed ]

A patient with Multiple endocrine neoplasia type 2B, presenting with mucosal neuromas. Mucosal Neuromas.png
A patient with Multiple endocrine neoplasia type 2B, presenting with mucosal neuromas.

Unlike Marfan syndrome, the cardiovascular system and the lens of the eye are unaffected.[ citation needed ] Mucosal neuromas are the most consistent and distinctive feature, appearing in 100% of patients. [11] Usually there are numerous yellowish-white, sessile, painless nodules on the lips or tongue, with deeper lesions having normal coloration. There may be enough neuromas in the body of the lips to produce enlargement and a "blubbery lip" appearance. Similar nodules may be seen on the sclera and eyelids.[ citation needed ]

Histologically, neuromata contain a characteristic adventitious plaque of tissue composed of hyperplastic, interlacing bands of Schwann cells and myelinated fibers overlay the posterior columns of the spinal cord. [12] Mucosal neuromas are made up of nerve cells, often with thickened perineurium, intertwined with one another in a plexiform pattern. This tortuous pattern of nerves is seen within a background of loose endoneurium-like fibrous stroma.[ citation needed ]

Causes

Variations in the RET proto-oncogene cause MEN2B. In recent decades no case of MEN2B has been reported that lacks such a variation. The M918T variant alone is responsible for approximately 95% of cases. [13] All DNA variants that cause MEN2B are thought to enhance signaling through the RET protein, which is a receptor molecule found on cell membranes, whose ligands are part of the transforming growth factor beta signaling system.[ citation needed ]

About half of cases are inherited from a parent as an autosomal dominant trait. The other half appear to be spontaneous mutations, [2] usually arising in the paternal allele, [14] particularly from older fathers. [2] The sex ratio in de novo cases is also uneven: sons are twice as likely to develop MEN 2B as daughters. [2]

Diagnosis

Differential diagnosis

DNA testing is now the preferred method of establishing a diagnosis for MEN 2B, and is thought to be almost 100% sensitive and specific. Gordon et al. reported cases of a difference disease—the "multiple mucosal neuroma syndrome"—having the physical phenotype of MEN2B, but without variations in the RET gene and without malignancy. [15]

MEN2B should be entertained as a diagnosis whenever a person is found to have either medullary thyroid carcinoma or pheochromocytoma. Before DNA testing became available, measurement of serum calcitonin was the most important laboratory test for MEN2B. Calcitonin is produced by the "C" cells of the thyroid, which, because they are always hyperplastic or malignant in MEN2B, produce more calcitonin than normal. Calcitonin levels remain a valuable marker to detect recurrence of medullary thyroid carcinoma after thyroidectomy.[ citation needed ]

Luxol fast blue staining identifies myelin sheathing of some fibers, and lesional cells react immunohistochemically for S-100 protein, collagen type IV, vimentin, NSE, and neural filaments. More mature lesions will react also for EMA, indicating a certain amount of perineurial differentiation. Early lesions, rich in acid mucopolysaccharides, stain positively with alcian blue. When medullary thyroid cancer is present, levels of the hormone calcitonin are elevated in serum and urine. [13] Under the microscope, tumors may closely resemble traumatic neuroma, but the streaming fascicles of mucosal neuroma are usually more uniform and the intertwining nerves of the traumatic neuroma lack the thick perineurium of the mucosal neuroma. [16] Inflammatory cells are not seen in the stroma and dysplasia is not present in the neural tissues.[ citation needed ]

Treatment

Without treatment, persons with MEN2B die prematurely. Details are lacking, owing to the absence of formal studies, but it is generally assumed that death in the 30s is typical unless prophylactic thyroidectomy and surveillance for pheochromocytoma are performed (see below). The range is quite variable, however: death early in childhood can occur, and a few untreated persons have been diagnosed in their 50s. [17] Recently, a larger experience with the disease "suggests that the prognosis in an individual patient may be better than previously considered." [18]

Thyroidectomy is the mainstay of treatment, and should be performed without delay as soon as a diagnosis of MEN2B is made, even if no malignancy is detectable in the thyroid. Without thyroidectomy, almost all patients with MEN2B develop medullary thyroid cancer, in a more aggressive form than MEN 2A. [13] [19] The ideal age for surgery is 4 years old or younger, since cancer may metastasize before age 10. [14]

Pheochromocytoma - a hormone secreting tumor of the adrenal glands - is also present in 50% of cases. [14] Affected individuals are encouraged to get yearly screenings for thyroid and adrenal cancer.[ citation needed ]

Because prophylactic thyroidectomy improves survival, blood relatives of a person with MEN2B should be evaluated for MEN2B, even if lacking the typical signs and symptoms of the disorder.[ citation needed ]The mucosal neuromas of this syndrome are asymptomatic and self-limiting, and present no problem requiring treatment. They may, however, be surgically removed for aesthetic purposes or if they are being constantly traumatized.[ citation needed ]

Society and culture

Abraham Lincoln hypothesis

In 2007, Dr. John Sotos proposed that President Abraham Lincoln had MEN2B. [20] This theory suggests Lincoln had all the major features of the disease: a marfan-like body habitus, large, bumpy lips, constipation, muscular hypotonia, a history compatible with cancer and a family history of the disorder - his sons Eddie, Willie, and Tad, and probably his mother. The "mole" on Lincoln's right cheek, the asymmetry of his face, his large jaw, his drooping eyelid, and "pseudo-depression" are also suggested as manifestations of MEN2B. Lincoln's longevity (dying at 56 of a gunshot wound and without any apparent suggestion of ill health otherwise) is the principal challenge to the MEN2B theory, which could be proven by DNA testing. [21] [22]

See also

Related Research Articles

<span class="mw-page-title-main">Thyroid neoplasm</span> Medical condition

Thyroid neoplasm is a neoplasm or tumor of the thyroid. It can be a benign tumor such as thyroid adenoma, or it can be a malignant neoplasm, such as papillary, follicular, medullary or anaplastic thyroid cancer. Most patients are 25 to 65 years of age when first diagnosed; women are more affected than men. The estimated number of new cases of thyroid cancer in the United States in 2010 is 44,670 compared to only 1,690 deaths. Of all thyroid nodules discovered, only about 5 percent are cancerous, and under 3 percent of those result in fatalities.

<span class="mw-page-title-main">Thyroidectomy</span> Surgical procedure involving partial or complete removal of the thyroid

A thyroidectomy is an operation that involves the surgical removal of all or part of the thyroid gland. In general surgery, endocrine or head and neck surgeons often perform a thyroidectomy when a patient has thyroid cancer or some other condition of the thyroid gland or goiter. Other indications for surgery include cosmetic, or symptomatic obstruction. Thyroidectomy is a common surgical procedure that has several potential complications or sequelae including: temporary or permanent change in voice, temporary or permanently low calcium, need for lifelong thyroid hormone replacement, bleeding, infection, and the remote possibility of airway obstruction due to bilateral vocal cord paralysis. Complications are uncommon when the procedure is performed by an experienced surgeon.

<span class="mw-page-title-main">Multiple endocrine neoplasia</span> Medical condition

Multiple endocrine neoplasia is a condition which encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign. Benign or malignant tumors of nonendocrine tissues occur as components of some of these tumor syndromes.

<span class="mw-page-title-main">Calcitonin</span> Amino acid peptide hormone secreted by the thyroid gland

Calcitonin is a 32 amino acid peptide hormone secreted by parafollicular cells (also known as C cells) of the thyroid (or endostyle) in humans and other chordates in the ultimopharyngeal body. It acts to reduce blood calcium (Ca2+), opposing the effects of parathyroid hormone (PTH).

<span class="mw-page-title-main">Pentagastrin</span> Chemical compound

Pentagastrin is a synthetic polypeptide that has effects like gastrin when given parenterally. It stimulates the secretion of gastric acid, pepsin, and intrinsic factor, and has been used as a diagnostic aid as the pentagastrin-stimulated calcitonin test.

<span class="mw-page-title-main">Paraganglioma</span> Medical condition

A paraganglioma is a rare neuroendocrine neoplasm that may develop at various body sites. When the same type of tumor is found in the adrenal gland, they are referred to as a pheochromocytoma. They are rare tumors, with an overall estimated incidence of 1/300,000. There is no test that determines benign from malignant tumors; long-term follow-up is therefore recommended for all individuals with paraganglioma.

Neuroendocrine cells are cells that receive neuronal input and, as a consequence of this input, release messenger molecules (hormones) into the blood. In this way they bring about an integration between the nervous system and the endocrine system, a process known as neuroendocrine integration. An example of a neuroendocrine cell is a cell of the adrenal medulla, which releases adrenaline to the blood. The adrenal medullary cells are controlled by the sympathetic division of the autonomic nervous system. These cells are modified postganglionic neurons. Autonomic nerve fibers lead directly to them from the central nervous system. The adrenal medullary hormones are kept in vesicles much in the same way neurotransmitters are kept in neuronal vesicles. Hormonal effects can last up to ten times longer than those of neurotransmitters. Sympathetic nerve fiber impulses stimulate the release of adrenal medullary hormones. In this way the sympathetic division of the autonomic nervous system and the medullary secretions function together.

<span class="mw-page-title-main">Multiple endocrine neoplasia type 1</span> Medical condition

Multiple endocrine neoplasia type 1 (MEN-1) is one of a group of disorders, the multiple endocrine neoplasias, that affect the endocrine system through development of neoplastic lesions in pituitary, parathyroid gland and pancreas. Individuals suffering from this disorder are prone to developing multiple endocrine and nonendocrine tumors. It was first described by Paul Wermer in 1954.

<span class="mw-page-title-main">Multiple endocrine neoplasia type 2</span> Medical condition

Multiple endocrine neoplasia type 2 is a group of medical disorders associated with tumors of the endocrine system. The tumors may be benign or malignant (cancer). They generally occur in endocrine organs, but may also occur in endocrine tissues of organs not classically thought of as endocrine. MEN2 is a sub-type of MEN and itself has sub-types, as discussed below. Variants in MEN2A have been associated with Hirschsprung disease. Screening for this condition can begin as young as eight years old for Pheochromocytoma.

<span class="mw-page-title-main">Hürthle cell</span> Medical condition

A Hürthle cell is a cell in the thyroid that is often associated with Hashimoto's thyroiditis as well as benign and malignant tumors. This version is a relatively rare form of differentiated thyroid cancer, accounting for only 3-10% of all differentiated thyroid cancers. Oncocytes in the thyroid are often called Hürthle cells. Although the terms oncocyte, oxyphilic cell, and Hürthle cell are used interchangeably, Hürthle cell is used only to indicate cells of thyroid follicular origin.

<span class="mw-page-title-main">Papillary thyroid cancer</span> Medical condition

Papillary thyroid cancer is the most common type of thyroid cancer, representing 75 percent to 85 percent of all thyroid cancer cases. It occurs more frequently in women and presents in the 20–55 year age group. It is also the predominant cancer type in children with thyroid cancer, and in patients with thyroid cancer who have had previous radiation to the head and neck. It is often well-differentiated, slow-growing, and localized, although it can metastasize.

<span class="mw-page-title-main">Neuroendocrine tumor</span> Medical condition

Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the pancreas, lung, and the rest of the body.

<span class="mw-page-title-main">Endocrine disease</span> Medical condition

Endocrine diseases are disorders of the endocrine system. The branch of medicine associated with endocrine disorders is known as endocrinology.

<span class="mw-page-title-main">RET proto-oncogene</span> Mammalian protein

The RETproto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor (GDNF) family of extracellular signalling molecules. RET loss of function mutations are associated with the development of Hirschsprung's disease, while gain of function mutations are associated with the development of various types of human cancer, including medullary thyroid carcinoma, multiple endocrine neoplasias type 2A and 2B, pheochromocytoma and parathyroid hyperplasia.

<span class="mw-page-title-main">Adrenal tumor</span> Medical condition

An adrenal tumor or adrenal mass is any benign or malignant neoplasms of the adrenal gland, several of which are notable for their tendency to overproduce endocrine hormones. Adrenal cancer is the presence of malignant adrenal tumors, and includes neuroblastoma, adrenocortical carcinoma and some adrenal pheochromocytomas. Most adrenal pheochromocytomas and all adrenocortical adenomas are benign tumors, which do not metastasize or invade nearby tissues, but may cause significant health problems by unbalancing hormones.

<span class="mw-page-title-main">Medullary thyroid cancer</span> Malignant thyroid neoplasm originating from C-cells

Medullary thyroid cancer is a form of thyroid carcinoma which originates from the parafollicular cells, which produce the hormone calcitonin. Medullary tumors are the third most common of all thyroid cancers and together make up about 3% of all thyroid cancer cases. MTC was first characterized in 1959.

<span class="mw-page-title-main">Parathyroid carcinoma</span> Medical condition

Parathyroid carcinoma is a rare cancer resulting in parathyroid adenoma to carcinoma progression. It forms in tissues of one or more of the parathyroid glands.

<span class="mw-page-title-main">Thyroid cancer</span> Medical condition

Thyroid cancer is cancer that develops from the tissues of the thyroid gland. It is a disease in which cells grow abnormally and have the potential to spread to other parts of the body. Symptoms can include swelling or a lump in the neck. Cancer can also occur in the thyroid after spread from other locations, in which case it is not classified as thyroid cancer.

Endocrine oncology refers to a medical speciality dealing with hormone producing tumors, i.e. a combination of endocrinology and oncology.

References

  1. ↑ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 858. ISBN   978-1-4160-2999-1.
  2. 1 2 3 4 Carlson KM, Bracamontes J, Jackson CE, et al. (December 1994). "Parent-of-origin effects in multiple endocrine neoplasia type 2B". Am. J. Hum. Genet. 55 (6): 1076–82. PMC   1918453 . PMID   7977365.
  3. ↑ Wagenmann A. (1922). "Multiple neurome des Auges und der Zunge". Ber Dtsch Ophthalmol Ges. 43: 282–5.
  4. ↑ Williams ED (1965). "A review of 17 cases of carnicoma of the thyroid and phaeochromocytoma". J Clin Pathol. 18 (3): 288–292. doi:10.1136/jcp.18.3.288. PMC   472926 . PMID   14304238.
  5. ↑ Williams, E. D., Pollock, D. J. (1966). "Multiple mucosal neuromata with endocrine tumours: a syndrome allied to von Recklinghausen's disease". J. Pathol. Bacteriol. 91 (1): 71–80. doi:10.1002/path.1700910109. PMID   4957444.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ↑ Fryns JP, Chrzanowska K (October 1988). "Mucosal neuromata syndrome (MEN type IIb (III))". J. Med. Genet. 25 (10): 703–6. doi:10.1136/jmg.25.10.703. PMC   1051565 . PMID   2906373.
  7. ↑ Schimke RN, Hartmann WH, Prout TE, Rimoin DL (1968). "Syndrome of bilateral pheochromocytoma, medullary thyroid carcinoma and multiple neuromas. A possible regulatory defect in the differentiation of chromaffin tissue". N. Engl. J. Med. 279 (1): 1–7. doi:10.1056/NEJM196807042790101. PMID   4968712.
  8. ↑ Marx, Stephen J (2011). "Chapter 41: Multiple endocrine neoplasia". In Melmed, Shlomo (ed.). Williams Textbook of Endocrinology, 12th ed. pp. 1728–1767.
  9. ↑ Moline J, Eng C (2011). "Multiple endocrine neoplasia type 2: an overview". Genetics in Medicine. 13 (9): 755–764. doi: 10.1097/GIM.0b013e318216cc6d . PMID   21552134. S2CID   22402472.
  10. ↑ Martino Ruggieri (2005). Neurocutaneous Disorders : The Phakomatoses. Berlin: Springer. ISBN   978-3-211-21396-4. - Chapter: Multiple Endocrine Neoplasia Type 2B by Electron Kebebew, Jessica E. Gosnell and Emily Reiff. Pages 695-701. This reference quotes a prevalence of 1 in 40,000, but this figure is inconsistent with the same reference's calculated incidence of 4 per 100 million per year for MEN2B.
  11. ↑ Pujol RM, Matias-Guiu X, Miralles J, Colomer A, de Moragas JM (August 1997). "Multiple idiopathic mucosal neuromas: a minor form of multiple endocrine neoplasia type 2B or a new entity?". J. Am. Acad. Dermatol. 37 (2 Pt 2): 349–52. doi:10.1016/S0190-9622(97)70025-2. PMID   9270546.
  12. ↑ Dyck, PJ (October 1979). "Multiple endocrine neoplasia, type 2b: phenotype recognition; neurological features and their pathological basis". Annals of Neurology. 6 (4): 302–314. doi:10.1002/ana.410060404. PMID   554522. S2CID   24328061.
  13. 1 2 3 Sperling, Mark A. (2008). Pediatric Endocrinology (3 ed.). Elsevier Health Sciences. pp. 246–7. ISBN   978-1-4160-4090-3.
  14. 1 2 3 Morrison PJ, Nevin NC (September 1996). "Multiple endocrine neoplasia type 2B (mucosal neuroma syndrome, Wagenmann-Froboese syndrome)". J. Med. Genet. 33 (9): 779–82. doi:10.1136/jmg.33.9.779. PMC   1050735 . PMID   8880581.
  15. ↑ Gordon CM, Majzoub JA, Marsh DJ, Mulliken JB, Ponder BA, Robinson BG, Eng C (January 1998). "Four cases of mucosal neuroma syndrome: multiple endocrine neoplasm 2B or not 2B?". J Clin Endocrinol Metab. 83 (1): 17–20. doi: 10.1210/jcem.83.1.4504 . PMID   9435410.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ↑ R. L. Miller; N. J. Burzynski; B. L. Giammara (1977). "The ultrastructure of oral neuromas in multiple mucosal neuromas, pheochromocytoma, medullary thyroid carcinoma syndrome". Journal of Oral Pathology & Medicine. 6 (5): 253–63. doi:10.1111/j.1600-0714.1977.tb01647.x. PMID   409817. Archived from the original on 13 October 2012.
  17. ↑ Sizemore GW, Carney JA, Gharib H, Capen CC (1992). "Multiple endocrine neoplasia type 2B: eighteen-year follow-up of a four-generation family". Henry Ford Hosp Med J. 40 (3–4): 236–244. PMID   1362413.
  18. ↑ Hoff, AO; Gagel, RF (2006). "Chapter 192: Multiple endocrine neoplasia type 2". In DeGroot, LJ; Jameson, JL (eds.). Endocrinology (5th ed.). Philadelphia: Elsevier-Saunders. pp.  3533–3550. ISBN   978-0721603766.
  19. ↑ Lester W. Burket; Martin S. Greenberg; Michaël Glick; Jonathan A. Ship (2008). Burket's oral medicine (11 ed.). PMPH-USA. p. 141. ISBN   978-1-55009-345-2.
  20. ↑ Sotos, JG (2008). The Physical Lincoln: Finding the Genetic Cause of Abraham Lincoln's Height, Homeliness, Pseudo-Depression, and Imminent Cancer Death. Mount Vernon, VA: Mt. Vernon Book Systems.
  21. ↑ Scientist Wants to Test Abraham Lincoln's Bloodstained Pillow for Cancer Discover Magazine 20 April 2009
  22. ↑ Lincoln's Shroud of Turin, Philadelphila Inquirer, 13 April 2009
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