Forms Of Multiple Endocrine Neoplasia Research Articles

Hyperparathyroidism-jaw Tumor Syndrome: An Overlooked Cause of Severe Hypercalcemia

Ossifying fibromas of the maxillofacial bones are an uncommon form of benign neoplasm usually treated by surgical excision. Up to 30% of patients with hyperparathyroidism-jaw tumor syndrome, a rare form of multiple endocrine neoplasia resulting from autosomal dominant inactivating mutation of the Hrpt2 tumor suppressor gene, initially present with ossifying fibromas. Coincident hypercalcemia because of the presence of parathyroid adenoma is common in these patients, of whom 15% may have or may develop parathyroid carcinoma. The authors present a case of severe postsurgical hypercalcemia after removal of a large maxillary ossifying fibroma in a patient with previously unrecognized hyperparathyroidism-jaw tumor AU3 syndrome.

Chromosomal rearrangements and the pathogenesis of differentiated thyroid cancer

The majority of thyroid cancers arise from the follicular cells of the thyroid gland, which yield a wide variety of distinct morphotypes, ranging from relatively indolent lesions to the most malignant forms of cancer known. The remaining primary thyroid cancers arise from C cells within the gland and result primarily from mutations of the RET protooncogene, germ line mutations of which give rise to the various forms of multiple endocrine neoplasia. The most common of the follicular cell-derived cancers are papillary carcinomas, (PTC), followed by follicular carcinomas (FTC) and its Hurthle cell variant (HCC) and finally anaplastic carcinomas (ATC). The pathogenesis of many thyroid cancers, of both PTC and FTC morphotype, involves chromosomal translocations. Rearrangements of the RET protoconcogene are known to be involved in the pathogenesis of ca. 50% of PTC. A similar proportion of FTC have been associated with a t(2;3)(q13;p25) translocation, fusing the thyroid-specific transcription factor PAX8 with the peroxisome proliferator-activated receptor gamma (PPARγ) nuclear receptor, a ubiquitously expressed transcription factor. These rearrangements have analogy with translocations in erythropoetic cells, which form the only other known group of human malignancies that are largely the result of chromosomal translocation events. In this review we compare and contrast the oncogenic properties of thyroid and erythroid chromosomal transformations and speculate on mechanisms leading to their formation.

MEN-4 and other multiple endocrine neoplasias due to cyclin-dependent kinase inhibitors (p27Kip1 and p18INK4C) mutations

Cyclin-dependent kinase inhibitors (CDKIs) are known targets to become deregulated in various tumour types, including endocrine tumours. Typically, these cell cycle regulators are somatically inactivated in sporadic endocrine tumours. Recently, it became known that certain CDKI genes cause inherited susceptibility to endocrine neoplasia. Multiple endocrine neoplasia type 4 (MEN4) emerged as a novel form of multiple endocrine neoplasia, caused by mutations in the CDKI gene CDKN1B/p27(Kip1). The MEN4 phenotype remains unclear, but all MEN4 patients identified thus far present with parathyroid involvement, and less typically with pituitary adenomas and other endocrine features. Moreover, the CDKI gene CDKN2C/p18(INK4C) has been also implicated in endocrine neoplasia susceptibility. This review presents the recent advances in these novel MEN-related states and summarises the current knowledge of how these CDKIs may be implicated in endocrine neoplasia. In addition, it briefly presents data from Cdkn1b/p27(Kip1) and Cdkn2c/p18(INK4C) murine models, which strongly support the protective role of these inhibitors against endocrine tumourigenesis.

The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney–Stratakis syndrome): molecular genetics and clinical implications

Carney triad (CT) describes the association of paragangliomas (PGLs) with gastrointestinal stromal tumours (GISTs) and pulmonary chondromas (PCH). A number of other lesions have been described in the condition including pheochromocytomas, oesophageal leiomyomas and adrenocortical adenomas; CT is a novel form of multiple endocrine neoplasia (MEN), a genetic condition with a female predilection. Inactivating mutations of the mitochondrial complex II succinate dehydrogenase (SDH) enzyme subunits SDHB, SDHC and SDHD have been found in familial and sporadic PGLs, and gain-of-function mutations of the oncogenes c-kit (KIT) and platelet-derived growth factor receptor A (PDGFRA) cause sporadic and familial GISTs. We recently reported an international series of patients with CT, 34 females and three males (median age of presentation 21 years) who did not carry SDHA, SDHB, SDHC, SDHD, KIT or PDGFRA gene mutations. Comparative genomic hybridization revealed a number of DNA copy number changes. The most frequent and greatest contiguous change was a deletion within the 1pcen13-q21 region, which harbours the SDHC gene. Another frequent change was loss of 1p. Although GISTs showed more frequent losses of 1p than PGLs, the pattern of chromosomal changes was similar in the two tumours despite their different tissue origin and histology; the findings were consistent with a common genetic aetiology of these two tumours in CT. In a separate condition, in which the association (or dyad) of GISTs with PGLs is inherited in an autosomal dominant manner (Carney-Stratakis syndrome, CSS), germline mutations of the SDHB, SDHC and SDHD genes (but not KIT or PDFGRA) were found; GISTs in this condition were caused by SDH deficiency. We conclude that CT is a novel MEN syndrome whose genetic defect remains elusive. CSS is caused by SDH defects, suggesting that sarcomas (GISTs) can be caused by defective mitochondrial oxidation, consistent with recent data implicating this enzyme in a variety of endocrine and other tumours. The above have clinical implications (i) for patients with GISTs that are cKIT- and PDGFRA-mutation negative: these tumours are usually resistant to treatment with currently available tyrosine kinase inhibitors and may be part of a syndrome such as CT or CSS; and (ii) for patients with an inherited PGL syndrome, family history should be explored to identify any other tumours in the family, and in particular other endocrine lesions and GISTs.

Possible association between Carney complex and multiple endocrine neoplasia type 1 phenotypes

Carney Complex (CNC) and Multiple Endocrine Neoplasia type 1 (MEN1) are forms of multiple endocrine neoplasia of dominant autosomal inheritance. Diagnosis of CNC occurs when two major criteria (lentiginoses, primary pigmented nodular adrenocortical disease, cardiac and cutaneous myxomas, acromegaly, testicular neoplasias, thyroid cancer) are observed and/or a major criterion associated with a supplementary criterion (affected relative, PRKAR1A gene mutation) occurs. On the other hand, diagnosis for MEN1 occurs through detection of two or more tumors located at the pituitary gland, parathyroid and/or pancreatic cells. The present case describes a 55 year-old male patient, diagnosed with acromegaly, primary hyperparathyroidism and papillary thyroid cancer, exhibiting components that meet the diagnostic criteria of both conditions described. Despite the occurrence of only one sporadic association or the acromegaly per se being responsible for the papillary cancer, new molecular mechanisms may not be ruled out.

Minimal-invasive Chirurgie des Thymus

There are absolute and relative indications for complete removal of the thymus gland. In the complex therapy of autoimmune-related myasthenia gravis, thymectomy plays a central role and is performed with relative indication. In case of thymoma with or without myasthenia, thymectomy is absolutely indicated. Thymus resection is further necessary for cases of hyperparathyroidism with ectopic intrathymic parathyroids or with certain forms of multiple endocrine neoplasia. The transcervical operation technique traditionally reflected the well-founded desire for minimal invasiveness for thymectomy. Due to the requirement of radicality however, most of these operations were performed using sternotomy. With the evolution of therapeutic thoracoscopy in thoracic surgery, several pure or extended minimally invasive operation techniques for thymectomy have been developed. At present uni- or bilateral, subxiphoid, and modified transcervical single or combination thoracoscopic techniques are in use. Recently a very precise new level of thoracoscopic operation technique was developed using robotic-assisted surgery. There are special advantages of this technique for thymectomy. An overview of the development and experiences with minimally invasive thymectomy is presented, including data from the largest series published so far.

Chromosomal rearrangements and the pathogenesis of differentiated thyroid cancer

The majority of thyroid cancers arise from the follicular cells of the thyroid gland, which yield a wide variety of distinct morphotypes, ranging from relatively indolent lesions to the most malignant forms of cancer known. The remaining primary thyroid cancers arise from C cells within the gland and result primarily from mutations of the RET protooncogene, germ line mutations of which give rise to the various forms of multiple endocrine neoplasia. The most common of the follicular cell-derived cancers are papillary carcinomas, (PTC), followed by follicular carcinomas (FTC) and its Hurthle cell variant (HCC) and finally anaplastic carcinomas (ATC). The pathogenesis of many thyroid cancers, of both PTC and FTC morphotype, involves chromosomal translocations. Rearrangements of the RET protoconcogene are known to be involved in the pathogenesis of ca. 50% of PTC. A similar proportion of FTC have been associated with a t(2;3)(q13;p25) translocation, fusing the thyroid-specific transcription factor PAX8 with the peroxisome proliferator-activated receptor gamma (PPARγ) nuclear receptor, a ubiquitously expressed transcription factor. These rearrangements have analogy with translocations in erythropoetic cells, which form the only other known group of human malignancies that are largely the result of chromosomal translocation events. In this review we compare and contrast the oncogenic properties of thyroid and erythroid chromosomal transformations and speculate on mechanisms leading to their formation.

Rare syndromes

Dermatologists may also encounter patients presenting with skin lesions that reflect an underlying endocrine disorder not commonly seen in daily practice. Some of these endocrine disorders include glucagonoma, neurofibromatosis type 1, McCune-Albright syndrome, multiple endocrine neoplasia, the Carney complex, carcinoid tumors, and mastocytosis. The clinical syndrome classically associated with glucagonoma includes necrolytic migratory erythema, weight loss, diabetes mellitus, anemia, cheilitis, venous thrombosis, and neuropsychiatric symptoms. The hallmarks of neurofibromatosis type 1 are the multiple café-au-lait spots and associated cutaneous neurofibromas. Other presenting features include freckling, peripheral neurofibromas, Lisch nodules, bone abnormalities, tumors, neurologic abnormalities and hypertension. McCune-Albright syndrome is characterized by café-au-lait spots, polyostotic fibrous dysplasia, sexual precocity, and hyperfunction of multiple endocrine glands. Multiple endocrine neoplasia type 2A is characterized by medullary thyroid cancer, pheochromocytoma, and primary parathyroid hyperplasia. In some patients with multiple endocrine neoplasia type 2A, cutaneous lichen amyloidosis may also be present. Multiple endocrine neoplasia type 2B is characterized by medullary thyroid cancer and pheochromocytoma but not hyperparathyroidism. The syndrome also includes mucosal neuromas, typically involving the lips and tongue, intestinal ganglioneuromas and a marfanoid habitus. Multiple endocrine neoplasia type 1 is an autosomal dominant predisposition to tumors of the parathyroid glands (four-gland hyperplasia), anterior pituitary, and pancreatic islet cells; hence, the mnemonic device of the “3 Ps”; multiple cutaneous lesions (angiofibromas and collagenomas) are frequent in patients with multiple endocrine neoplasia type 1. Carney complex may be viewed as a form of multiple endocrine neoplasia because affected patients often have tumors of two or more endocrine glands, including primary pigmented nodular adrenocortical disease (some with Cushing's syndrome), pituitary adenoma, testicular neoplasms, thyroid adenoma or carcinoma, and ovarian cysts. Additional unusual manifestations include psammomatous melanotic schwannoma, breast ductal adenoma, and a rare bone tumor, osteochondromyxoma. Carcinoid syndrome is the term applied to a constellation of symptoms mediated by various humoral factors elaborated by some carcinoid tumors; the major manifestations are diarrhea, flushing, bronchospasm, and cardiac valvular lesions. Mast cell diseases include all disorders of mast cell proliferation. These diseases can be limited to the skin, referred to as “cutaneous mastocytosis,” or involve extracutaneous tissues, called “systemic mastocytosis.” Patients present with urticaria pigmentosa, mastocytoma, or diffuse cutaneous mastocytosis. Systemic involvement may be gastronintestinal, hematologic, neurologic, and skeletal.

Protein kinase A and its role in human neoplasia: the Carney complex paradigm.

The type 1 alpha regulatory subunit (R1alpha) of cAMP-dependent protein kinase A (PKA) (PRKAR1A) is an important regulator of the serine-threonine kinase activity catalyzed by the PKA holoenzyme. Carney complex (CNC) describes the association 'of spotty skin pigmentation, myxomas, and endocrine overactivity'; CNC is in essence the latest form of multiple endocrine neoplasia to be described and affects the pituitary, thyroid, adrenal and gonadal glands. Primary pigmented nodular adrenocortical disease (PPNAD), a micronodular form of bilateral adrenal hyperplasia that causes a unique, inherited form of Cushing syndrome, is also the most common endocrine manifestation of CNC. CNC and PPNAD are genetically heterogeneous but one of the responsible genes is PRKAR1A, at least for those families that map to 17q22-24 (the chromosomal region that harbors PRKAR1A). CNC and/or PPNAD are the first human diseases to be caused by mutations in one of the subunits of the PKA holoenzyme. Despite the extensive literature on R1alpha and PKA, little is known about their potential involvement in cell cycle regulation, growth and/or proliferation. The presence of inactivating germline mutations and the loss of its wild-type allele in CNC lesions indicated that PRKAR1A could function as a tumor-suppressor gene in these tissues. However, there are conflicting data in the literature about PRKAR1A's role in human neoplasms, cancer cell lines and animal models. In this report, we review briefly the genetics of CNC and focus on the involvement of PRKAR1A in human tumorigenesis in an effort to reconcile the often diametrically opposite reports on R1alpha.

Medullary Thyroid Carcinoma: Nationwide Japanese Survey of 634 Cases in 1996 and 271 Cases in 2002

Medullary thyroid carcinoma (MTC) occurs sporadically or as an inherited disease, with the latter occurring in the form of multiple endocrine neoplasia (MEN) type 2A, MEN type 2B, or familial non-MEN medullary carcinoma (FMTC). MTC is inherited as an autosomal dominant trait and is associated with germline mutations of the RET proto-oncogene. Genetic testing identifies carriers of the mutant gene and enables preventive thyroidectomy. A nationwide questionnaire-based survey was conducted in 1996 and again in 2002, and we report here the results of the two surveys that characterize the clinical course of the inherited form of MTC. The data show a higher rate of inherited MTC than previously described, although MEN2A was found to be the most common inherited form of MTC, the same as in earlier studies. The most important finding was the difference in method of detection of MTC between the two surveys. Since the discovery of the genetic association with the disease, genetic testing has become the diagnostic method of choice, replacing indicators such as neck mass and elevated non-stimulated serum calcitonin level. Genetic testing enables early detection of the disease, which provides patients with the possibility of better outcome.

Gestational trophoblastic disease in Taiwan

Cyclin-dependent kinase inhibitors (CDKIs) are known targets to become deregulated in various tumour types, including endocrine tumours. Typically, these cell cycle regulators are somatically inactivated in sporadic endocrine tumours. Recently, it became known that certain CDKI genes cause inherited susceptibility to endocrine neoplasia. Multiple endocrine neoplasia type 4 (MEN4) emerged as a novel form of multiple endocrine neoplasia, caused by mutations in the CDKI gene CDKN1B/p27Kip1. The MEN4 phenotype remains unclear, but all MEN4 patients identified thus far present with parathyroid involvement, and less typically with pituitary adenomas and other endocrine features. Moreover, the CDKI gene CDKN2C/p18INK4C has been also implicated in endocrine neoplasia susceptibility. This review presents the recent advances in these novel MEN-related states and summarises the current knowledge of how these CDKIs may be implicated in endocrine neoplasia. In addition, it briefly presents data from Cdkn1b/p27Kip1 and Cdkn2c/p18INK4C murine models, which strongly support the protective role of these inhibitors against endocrine tumourigenesis.

Multiple endocrine neoplasia type 1 (MEN1)

Multiple endocrine neoplasia (1–3) is characterized by the occurrence of tumors involving two or more endocrine glands within a single patient. The disorder has previously been referred to as multiple endocrine adenopathy (MEA) or the pluriglandular syndrome. However, glandular hyperplasia and malignancy may also occur in some patients and the term multiple endocrine neoplasia (MEN) is now preferred. There are two major forms of multiple endocrine neoplasia referred to as type 1 and type 2 and each form is characterized by the development of tumors within specific endocrine glands (see Table 1). Thus, the combined occurrence of tumors of the parathyroid glands, the pancreatic islet cells, and the anterior pituitary is characteristic of multiple endocrine neoplasia type 1(MEN1), which is also referred to as Wermer’s syndrome. In addition to these tumors, adrenal cortical, carcinoid, facial angiofibromas, collagenomas, and lipomatous tumors have also been described in patients with MENI (3, 4). However, in multiple endocrine neoplasia type 2 (MEN2), which is also called Sipple’s syndrome, medullary thyroid carcinoma (MTC) occurs in association with phaeochromocytoma, and three clinical variants referred to as MEN2a, MEN2b and MTC-only are recognized (1, 5). In MEN2a, which is the most common variant, the development of MTC is associated with phaeochromocytoma and parathyroid tumors. However, in MEN2b parathyroid involvement is absent and the occurrence of MTC and phaeochromocytoma is found in association with a marfanoid habitus mucosal neuromas, medullated corneal fibers and intestinal autonomic ganglion dysfunction leading to a megacolon.

Development of a sequence-tagged site for the centromere of chromosome 10: its use in cytogenetic and physical mapping.

We sequenced the alphoid centromere probe p alpha 10RP8 (D10Z1), aligned it to three published consensus sequences, and developed a sequence-tagged site (STS), sJRH-2, based upon oligonucleotide primers having two 3' mismatches with these consensus sequences. Polymerase chain reaction (PCR) amplification using genomic DNA from a somatic cell hybrid panel representing all human chromosomes demonstrated amplification from only those cell lines containing chromosome 10. Fluorescence in situ hybridization of the amplified product demonstrated intense and specific hybridization of the PCR product to 10p11.1-q11.1. A human genomic yeast artificial chromosome (YAC) library was screened using the sJRH-2 PCR assay, and five clones were identified. Sequence analysis of one chimeric clone (consisting of DNA segments derived from chromosomes 5p and 10cen) confirmed specificity of the STS for the centromere of chromosome 10. sJRH-2 provides a convenient cytogenetic marker for chromosome 10, which will also be useful for physical mapping of the pericentromeric region of chromosome 10, a region that harbors the gene(s) for three forms of multiple endocrine neoplasia (types 2A, 2B, and familial medullary thyroid carcinoma). The GenBank accession number for the p alpha 10RP8 sequence is X63622.

Multiple Endocrine Neoplasia Type II With Zollinger-Ellison Syndrome Caused by a Solitary Pancreatic Gastrinoma

THERE are three familial forms of multiple endocrine neoplasia (MEN), all of which are inherited as autosomal dominant traits. Multiple endocrine neoplasia type I is characterized by hyperparathyroidism, pituitary tumors, pancreatic islet cell tumors, and other less common manifestations. 1,2 Multiple endocrine neoplasia type II is characterized by medullary carcinoma of the thyroid, pheochromocytoma, and hyperparathyroidism. 3,4 Patients with type III, otherwise named MEN type lib, are similar to patients with type II but also have mucosal neuromas and marfanoid habitus. 4,5 These three conditions are inherited separately and are distinct entities. Thus, mucosal neuromas are restricted to type IIb, pheochromocytoma and medullary thyroid carcinoma occur only in type II, and pituitary tumors and islet cell tumors occur only in type I. However, because increasing numbers of patients with syndromes are now being followed up, together with the increasing longevity of these patients, features