Multiple Endocrine Neoplasia Type

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The bilobate thyroid gland is located on the anterior surface of the trachea at the junction of the larynx and secretes a number of hormones essential for growth and development. Each lobe has many hollow spherical clusters (follicles) that are circumscribed by a single layer of cells. Parafollicular cells (C cells) occupy the spaces between follicles. The follicular cells synthesize and secrete several hormones, including thyroxine and triiodothyronine, which regulate metabolic rate and maintain the responsiveness of the cardiovascular system to nerve impulses. The parafollicular cells manufacture and release calcitonin, which regulates the concentration of calcium ions in the blood and other body fluids. Calcitonin decreases calcium ion concentrations, stimulates the production of bone, reduces the absorption of Ca2+ by the intestine, and stimulates the excretion of Ca2+ by the kidneys.

The incidence of both benign and malignant thyroid gland cancers is about 1 in 20,000 individuals worldwide. Cancers of the follicular and parafollicular cells are distinct biological entities. However, much research has focused on cancer of the parafollicular cells. Specifically, medullary thyroid cancer (MTC) is a parafollicular cell cancer with both autosomal dominant and sporadic forms. MTC usually is benign and treatable if detected early. The hereditary form of MTC is part of a cancer syndrome designated as multiple endocrine neoplasia type 2 (MEN2). Based on combinations of tumors in various MEN2 families, three MEN2 subtypes have been identified. In the first MEN2 subtype, the only cancer is MTC, and the subtype is called familial medullary thyroid cancer (FMTC). The second MEN2 subtype has three prevalent cancers and has been designated MEN2A. The types of MEN2A cancers are MTC, parathyroid gland cancer (parathyroid hyperplasia), and adrenal medulla cancer (pheochromocytoma), which are present in about 95%, 50%, and 30%, respectively, of MEN2A patients. Parathyroid hyperplasia effects the parathyroid glands, located on the posterior surface of the thyroid gland, that produce parathormone. This hormone increases calcium ion concentration in the blood, decreases blood phosphate concentration, stimulates the breakdown of bone, and, if the level of Ca2+ in the blood is abnormal, reduces the excretion of Ca2+ by the kidneys. The third MEN2 subtype is MEN2B and is rarely encountered. MEN2B individuals usually have MTC, pheochromocytoma, abnormal proliferation of ganglion cells of the intestinal tract (ganglioneuromas), and tumors (neuromas) of the lips, tongue, and the mucous membrane of the anterior surface of the eye. Parathyroid hyperplasia is not a feature of MEN2B. Onset of MEN2B is soon after birth, and the development of the tumors is very rapid. By contrast, FMTC is only evident 40 to 50 years after birth, with diarrhea as the most common symptom. With the MEN2A subtype, the different cancers appear when individuals are between 20 and 30 years old. Patients with the three MEN2A cancers suffer from diarrhea as a result of MTC, both irritability and hypertension caused by pheochromocytoma, and kidney stones from parathyroid hyperplasia.

Linkage studies with MEN2 families, regardless of subtype, localized the putative gene to chromosome 10q11.2. Thus the three MEN2 subtypes probably represented mutations of the same gene or three closely linked genes. Previously, the RET (rearrangement during transfection) oncogene that encodes a tyrosine protein kinase receptor had also been mapped to 10q11.2, actually 10q11.21, and provided a likely candidate gene for the MEN2 cancers. The RET gene is expressed in kidney cells and both the central and peripheral nervous systems. A protein complex that includes the glial cell line-derived neurotrophic factor (GDNF) interacts with the RET protein to initiate a signal transduction pathway.

In addition, at about the same time that the MEN2-associated locus was discovered, the gene for an autosomal dominant condition called Hirschsprung disease (aganglionic megacolon), which affects about 1 in 5000 individuals, was mapped to chromosome 10q11.2. The principal phenotype of this noncancerous disorder is the absence of nerve cells (intrinsic ganglion cells) from a section of the terminal portion of the colon. Because there is no peristaltic movement in an aganglionic segment of a colon, waste material accumulates. In mild forms of Hirschsprung disease, a short segment of the colon is aganglionic, and constipation occurs. In severe cases, where a long segment of the colon lacks nerve cells, there may be complete colonic obstruction and abdominal distension. Often, with extreme colonic blockage, many small fissures develop and become infected. If untreated, the severe form is fatal when the colon ruptures. However, surgical removal of the aganglionic portion of the colon readily alleviates the condition. Interestingly, the primary phenotypic feature of Hirschsprung disease appears to be the converse of one of the sentinel features of the MEN2B subtype. With MEN2B, intestinal ganglionic cells proliferate and form enteric ganglioneuromas, whereas with Hirschsprung disease, a portion of the colon has no ganglionic cells.

Mutation analyses established that the RET gene was mutated in families with Hirschsprung disease, as well as in families with MEN2, regardless of the subtype. Therefore, a single gene is responsible for four different phenotypes. In a large study, more than 92% of 477 MEN2 families had a missense mutation in one of eight sites in the RET gene. The MEN2A mutations changed cysteine codons at sites 609, 611, 618, 620, 630, and 634. The amino acids encoded by these sites are near the transmembrane domain in the extracellular portion of the RET protein (Figure 16.10). Of these MEN2A mutations, which probably keep the protein tyrosine kinase activity turned on by abolishing the need for the receptor-specific factor, more than 85% are at codon 634, and, of these, 52% are C634R. More than 95% of the MEN2B mutations occur at codon 918 (M918T) within the tyrosine kinase domain of the RET protein. The RET mutations among the FMTC families are similar to those found in MEN2A individuals and include missense mutations at codons 618, 620, and



Signal sequence NH2

Cys-rich region TM

Tyrosine kinase domain

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