Multiple endocrine neoplasia type 2b
Encyclopedia
Multiple endocrine neoplasia type 3 (also known as "Mucosal neuromata with endocrine tumors", "Multiple endocrine neoplasia type 2B", "MEN2B", "Multiple mucosal neuroma syndrome", "Williams Syndrome", and "Wagenmann–Froboese syndrome") 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
, differentiated by the presence of oral and submucosal tumors in addition to endocrine tumors. It was first described by Wagenmann in 1922.
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,
followed by adrenal and thyroid
tumors after puberty. Medullary thyroid cancer
almost always occurs, and cancer of the adrenal glands (pheochromocytoma
) occurs in 50% of cases. In MEN 2b, the medullary cancer is very aggressive with most patients dying before developing either a phaeochromocytoma or hyperparathyroidism.
A variety of eponym
s 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 are no longer used in the medical literature.
It has an estimated prevalence
of 1 in 40.000.
allele, which suppresses cancer formation. The mutation - a single methionine
to threonine
substitution in the intracellular tyrosine kinase domain - alters the substrate specificity of intracellular signal transduction, conferring dominant cancer-causing activity.
Fifty percent of MEN 2B cases appear to be from a de novo mutation, a copying error that occurs in either the sperm or ovum
prior to fertilization. Like many de novo mutations, children born to older parents have an increased risk of spontaneous MEN 2B. The mutated gene is almost exclusively paternal, particularly from older fathers. The sex ratio is also uneven: sons are twice as likely to develop MEN 2B as daughters.
" body type and occasional muscle wasting.
Mucosal neuromas are the most consistent and distinctive feature, appearing in 100% of patients. Usually there are numerous yellowish-white, sessile, painless nodules on the lips or tongue, with deeper lesions having normal coloration. There may be enough neuroma
s in the body of the lips to produce enlargement and a "blubbery lip" appearance. Similar nodules may be seen on the sclera
and eyelids, sometimes causing th=
Findings at postmortem evaluation indicate that symptoms can be attributed to neuroma formation: a characteristic adventitious plaque of tissue composed of hyperplastic
, interlacing bands of Schwann cell
s and myelinated fibers overlay the posterior columns of the spinal cord. 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
.
is now the preferred method of establishing a diagnosis for MEN 2B. Identifying a mutated RET proto-oncogene
indicates a greater than 90% probability of developing multiple mucosal neuromata.
In the absence of DNA testing, 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, will stain positively with alcian blue
. When medullary thyroid cancer
is present, levels of the hormone calcitonin
are elevated in serum and urine. When adrenal cancer is present, serum levels of vanillylmandelic acid are increased and the ratio of epinephrine
to norepinephrine
is skewed.
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. Inflammatory cells are not seen in the stroma and dysplasia is not present in the neural tissues.
Almost all patients develop medullary thyroid cancer, in a more aggressive form than MEN 2A. Complete thyroidectomy
is often recommended at a young age, before malignant tumors develop. The ideal age for surgery is 4 years old or younger, since cancer may metastasize
before age 10. Pheochromocytoma
- cancer of the adrenal gland
s - is also present in 50% of cases. Affected individuals are encouraged to get yearly screenings for thyroid and adrenal cancer, and it is strongly suggested that other family members also be evaluated for MEN 2B.
suffered from MEN2B. This theory suggests Lincoln had all the major features of the disease: a marfan-like body shape, 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 is the principal challenge to the MEN2B theory, which could be proven by DNA testing. (Lincoln's reputed muscular strength does not contradict hypotonia; resting muscle tone is distinct from maximal muscle tension.)
Endocrine system
In physiology, the endocrine system is a system of glands, each of which secretes a type of hormone directly into the bloodstream to regulate the body. The endocrine system is in contrast to the exocrine system, which secretes its chemicals using ducts. It derives from the Greek words "endo"...
glands. It is the most severe type of multiple endocrine neoplasia
Multiple endocrine neoplasia
The term multiple endocrine neoplasia 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...
, differentiated by the presence of oral and submucosal tumors in addition to endocrine tumors. It was first described by Wagenmann in 1922.
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
Submucosa
In the gastrointestinal tract, the submucosa is the layer of dense irregular connective tissue or loose connective tissue that supports the mucosa, as well as joins the mucosa to the bulk of underlying smooth muscle .-Contents:Blood vessels, lymphatic vessels, and nerves will run through...
of almost all organs in the first decade of life,
followed by adrenal and thyroid
Thyroid
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
tumors after puberty. Medullary thyroid cancer
Medullary thyroid cancer
Medullary thyroid cancer is a form of thyroid carcinoma which originates from the parafollicular cells , which produce the hormone calcitonin....
almost always occurs, and cancer of the adrenal glands (pheochromocytoma
Pheochromocytoma
A pheochromocytoma or phaeochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands , or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually noradrenaline , and adrenaline to a lesser extent...
) occurs in 50% of cases. In MEN 2b, the medullary cancer is very aggressive with most patients dying before developing either a phaeochromocytoma or hyperparathyroidism.
A variety of eponym
Eponym
An eponym is the name of a person or thing, whether real or fictitious, after which a particular place, tribe, era, discovery, or other item is named or thought to be named...
s 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 are no longer used in the medical literature.
It has an estimated prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
of 1 in 40.000.
Causes
2A]], MEN 2B is inherited as an autosomal dominant trait, which means affected people have one affected parent, and possibly-affected siblings and children. However, about half of the cases appear to be spontaneous mutations. 95% of patients with MEN 2B have a single-point mutation of the RET proto-oncogeneRET proto-oncogene
The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor family of extracellular signalling molecules....
allele, which suppresses cancer formation. The mutation - a single methionine
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
to threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
substitution in the intracellular tyrosine kinase domain - alters the substrate specificity of intracellular signal transduction, conferring dominant cancer-causing activity.
Fifty percent of MEN 2B cases appear to be from a de novo mutation, a copying error that occurs in either the sperm or ovum
Ovum
An ovum is a haploid female reproductive cell or gamete. Both animals and embryophytes have ova. The term ovule is used for the young ovum of an animal, as well as the plant structure that carries the female gametophyte and egg cell and develops into a seed after fertilization...
prior to fertilization. Like many de novo mutations, children born to older parents have an increased risk of spontaneous MEN 2B. The mutated gene is almost exclusively paternal, particularly from older fathers. The sex ratio is also uneven: sons are twice as likely to develop MEN 2B as daughters.
Symptoms
Patients are tall and lanky, with a "marfanoidMarfan syndrome
Marfan syndrome is a genetic disorder of the connective tissue. People with Marfan's tend to be unusually tall, with long limbs and long, thin fingers....
" body type and occasional muscle wasting.
Mucosal neuromas are the most consistent and distinctive feature, appearing in 100% of patients. Usually there are numerous yellowish-white, sessile, painless nodules on the lips or tongue, with deeper lesions having normal coloration. There may be enough neuroma
Neuroma
A neuroma is a growth or tumor of nerve tissue. Just as the Latin word for swelling is now restricted to neoplasias, the equivalent Greek suffix -oma has shared in that fate. Thus, the typical modern usage of neuroma is for nerve tumors...
s in the body of the lips to produce enlargement and a "blubbery lip" appearance. Similar nodules may be seen on the sclera
Sclera
The sclera , also known as the white or white of the eye, is the opaque , fibrous, protective, outer layer of the eye containing collagen and elastic fiber. In the development of the embryo, the sclera is derived from the neural crest...
and eyelids, sometimes causing th=
Findings at postmortem evaluation indicate that symptoms can be attributed to neuroma formation: a characteristic adventitious plaque of tissue composed of hyperplastic
Hyperplasia
Hyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor....
, interlacing bands of Schwann cell
Schwann cell
Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system . Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle...
s and myelinated fibers overlay the posterior columns of the spinal cord. Mucosal neuromas are made up of nerve cells, often with thickened perineurium
Perineurium
In the peripheral nervous system, nerve fibers are each wrapped in a protective sheath known as the endoneurium. These are bundled together into groups known as fascicles, each surrounded by a protective sheath known as the perineurium. Several fascicles may be in turn bundled together with a blood...
, intertwined with one another in a plexiform pattern. This tortuous pattern of nerves is seen within a background of loose endoneurium-like fibrous stroma
Stroma (animal tissue)
In animal tissue, stroma refers to the connective, supportive framework of a biological cell, tissue, or organ.The stroma in animal tissue is contrasted with the parenchyma.Examples include:* Stroma of iris...
.
Differential Diagnosis
DNA testingDNA sequencing
DNA sequencing includes several methods and technologies that are used for determining the order of the nucleotide bases—adenine, guanine, cytosine, and thymine—in a molecule of DNA....
is now the preferred method of establishing a diagnosis for MEN 2B. Identifying a mutated RET proto-oncogene
RET proto-oncogene
The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor family of extracellular signalling molecules....
indicates a greater than 90% probability of developing multiple mucosal neuromata.
In the absence of DNA testing, Luxol fast blue staining identifies myelin sheathing
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
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, will stain positively with alcian blue
Alcian blue
Alcian blue , also called Alcian blue 8GX, Ingrain blue 1, and C.I. 74240, is a phthalocyanine . The dye stains acid mucopolysaccharides and glycosaminoglycans, for which it is one of the most widely used cationic dyes; the stained parts are blue to bluish-green...
. When medullary thyroid cancer
Medullary thyroid cancer
Medullary thyroid cancer is a form of thyroid carcinoma which originates from the parafollicular cells , which produce the hormone calcitonin....
is present, levels of the hormone calcitonin
Calcitonin
Calcitonin is a 32-amino acid linear polypeptide hormone that is producedin humans primarily by the parafollicular cells of the thyroid, and in many other animals in the ultimobranchial body. It acts to reduce blood calcium , opposing the effects of parathyroid hormone . Calcitonin has been found...
are elevated in serum and urine. When adrenal cancer is present, serum levels of vanillylmandelic acid are increased and the ratio of epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
to norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
is skewed.
Under the microscope, tumors may closely resemble traumatic neuroma
Traumatic neuroma
A traumatic neuroma is a type of neuroma which results from trauma to a nerve, usually during a surgical procedure. The most common oral locations are on the tongue and near the mental foramen of the mouth. They are relatively rare on the head and neck.It is also known as "pseudoneuroma"....
, 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. Inflammatory cells are not seen in the stroma and dysplasia is not present in the neural tissues.
Treatment and Prognosis
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.Almost all patients develop medullary thyroid cancer, in a more aggressive form than MEN 2A. Complete thyroidectomy
Thyroidectomy
A thyroidectomy is an operation that involves the surgical removal of all or part of the thyroid gland. Surgeons often perform a thyroidectomy when a patient has thyroid cancer or some other condition of the thyroid gland...
is often recommended at a young age, before malignant tumors develop. The ideal age for surgery is 4 years old or younger, since cancer may metastasize
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
before age 10. Pheochromocytoma
Pheochromocytoma
A pheochromocytoma or phaeochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands , or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually noradrenaline , and adrenaline to a lesser extent...
- cancer of the adrenal gland
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
s - is also present in 50% of cases. Affected individuals are encouraged to get yearly screenings for thyroid and adrenal cancer, and it is strongly suggested that other family members also be evaluated for MEN 2B.
Abraham Lincoln controversy
In 2007, Dr. John Sotos proposed that President Abraham LincolnAbraham Lincoln
Abraham Lincoln was the 16th President of the United States, serving from March 1861 until his assassination in April 1865. He successfully led his country through a great constitutional, military and moral crisis – the American Civil War – preserving the Union, while ending slavery, and...
suffered from MEN2B. This theory suggests Lincoln had all the major features of the disease: a marfan-like body shape, large, bumpy lips, constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
, muscular hypotonia
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
, a history compatible with cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
and a family history of the disorder - his sons Eddie
Edward Baker Lincoln
Edward Baker "Eddie" Lincoln was the second son of Abraham Lincoln and Mary Todd Lincoln. He was named after Lincoln's friend Edward Dickinson Baker, and the youngest Lincoln son to die....
, Willie
William Wallace Lincoln
William Wallace "Willie" Lincoln was the third son of Abraham Lincoln and Mary Todd Lincoln. He died at the age of 11. He was named after Mary's brother-in-law Dr. William Wallace.- Final illness and death :...
, and Tad
Tad Lincoln
Thomas "Tad" Lincoln was the fourth and youngest son of Abraham and Mary Lincoln. The nickname "Tad" was given to him by his father who found Thomas "as wriggly as a tadpole" when he was a baby. Tad was known to be impulsive, unrestrained, and did not attend school...
, 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 is the principal challenge to the MEN2B theory, which could be proven by DNA testing. (Lincoln's reputed muscular strength does not contradict hypotonia; resting muscle tone is distinct from maximal muscle tension.)
See also
- Multiple endocrine neoplasiaMultiple endocrine neoplasiaThe term multiple endocrine neoplasia 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...
- Multiple endocrine neoplasia type 1Multiple endocrine neoplasia type 1Multiple endocrine neoplasia type 1 or Wermer's syndrome is part of a group of disorders that affect the endocrine system.-Explanation:...
- Multiple endocrine neoplasia type 2a
- Multiple mucosal neuromataMultiple Mucosal NeuromataMultiple endocrine neoplasia type 3 is a genetic disease that causes multiple tumors on the mouth, eyes, and endocrine glands...
External links
- The Association for Multiple Endocrine Neoplasia Disorders (AMEND)
- A Personal Blog (Thyroid Cancer and Pheochromocytoma, MEN 2B)