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PubMed2001

Facial infiltrating lipomatosis.

Facial infiltrating lipomatosis is a rare congenital disorder in which mature lipocytes invade adjacent tissue. The phenotypic features include soft-tissue and skeletal hypertrophy, premature dental eruption, and regional macrodontia. There is a high risk for regrowth after resection that is, perforce, subtotal. The etiology, natural history, optimal management, and relationship to other disorders of fatty overgrowth are unclear. In this study, the clinical features, radiographic findings, histopathology, and postoperative results were analyzed in 13 patients with facial infiltrating lipomatosis. The condition was diagnosed in infancy (eight male subjects, five female subjects) and characterized by enlargement of the cheek (n = 12) or chin (n = 1). Other findings included cutaneous capillary blush (n = 9), ipsilateral macroglossia (n = 8), and mucosal neuromas (n = 6). Most patients had early eruption of ipsilateral deciduous and permanent teeth (n = 12). Computed tomography and magnetic resonance imaging showed an infiltrated soft-tissue mass of fatty density (n = 13) and skeletal overgrowth (n = 9). Multiple resection was performed on six patients (mean number of operations per patient, 2.5; range, one to six operations); regrowth and/or worsening of the capillary stain occurred in all six patients. Because surgical removal of the mass is usually unsuccessful, specific management of this condition will require insight into its etiopathogenesis. Given the presence of mucosal neuromas and lipomatosis, this study included testing for the known mutations in three entities that are associated with these soft-tissue findings (Cowden syndrome, Bannayan-Riley-Ruvalcava syndrome, and multiple endocrine neoplasia type 2B). Results of DNA analyses for these germline mutations were negative. It is more likely that this disorder is caused by a somatic mutation involving a local increase in growth factor(s).

Adipose Tissue↗
PubMedDate not supplied

Loss of heterozygosity on chromosomes 1 and 11 in sporadic pheochromocytomas.

Molecular genetic analysis was performed with 20 oncogene probes and 32 polymorphic DNA probes on tumor DNA samples from seven pheochromocytomas; namely, one multiple endocrine neoplasia type 2B, and two familial and four sporadic pheochromocytomas. No amplification or rearrangement of the oncogenes was detected in any of the tumors. However, loss of heterozygosity on chromosome 1p, 11p or 11q was detected in these cases. In addition, a locus related to ETS1 was deleted in two of the sporadic tumors. These results suggest that pheochromocytomas may be genetically heterogeneous, and that inactivation of unknown genes on chromosome 1p, 11p or 11q may contribute to their development.

Adrenal Gland Neoplasms↗
PubMed2003

[Intestinal ganglioneuromatosis diagnosed in adult patients].

AIM: Intestinal ganglioneuromatosis is essentially described in children and rarely in adults. The purpose of this study was to evaluate the clinical pathological patterns of intestinal ganglioneuromatosis diagnosed in adult patients. MATERIALS AND METHODS: Ten patients were included in this study (6 men, 4 woman; mean age=55.4 years). The diagnosis was established from ileocolorectal biopsies (n=5) or from a surgical specimen (n=5). An immunohistochemical study was performed with antibodies directed against S100 protein, synaptophysin, PGP9.5, neurofilament, tau protein, c-Kit and c-Ret. Clinical symptoms, endoscopic data and outcome were retrospectively reviewed. RESULTS: The diagnosis of intestinal ganglioneuromatosis was established solely on the basis of the microscopic examination in all 10 cases. Three patients presented with acute occlusion. The endoscopic examination showed unusual spasticity of the colon or colectasia in 5 cases, raspberry-like polyps in 2 cases and finger-like polyps in 3 cases. Ganglioneuromatosis was characterized by diffuse Schwann cell hyperplasia expressing S100 protein in close contact to nerve fibers expressing neurofilament, tau protein, synaptophysin, PGP9.5 and to ganglion cells expressing c-Ret. There was no hyperplasia of interstitial cells of Cajal. Intestinal ganglioneuromatosis was localized in the mucosa in 9 cases and extended through the entire intestinal wall in 1 case. The finger-like polyps corresponded to ganglioneuromatosis, while the raspberry-like polyps corresponded to adenomas. Two patients had von Recklinghausen's disease, 1 had multiple endocrine neoplasia type 2B and 1 had Cowden's disease. Intestinal ganglioneuromatosis was associated with nonfamilial adenomatous polyposis in 2 patients and colonic adenocarcinoma in 1 patient. The patients with finger-like polyps had no associated disease. CONCLUSION: Intestinal ganglioneuromatosis in adults is distinctive from that in children. In adults, intestinal ganglioneuromatosis is always a microscopic diagnosis although finger-like polyps observed at colonoscopy may be suggestive. Gastroenterologists must be aware of the higher risk of occlusion and intestinal neoplasia.

Adult↗
PubMedDate not supplied

Thick lips, bumpy tongue, and slipped capital femoral epiphysis--a deadly combination.

Multiple endocrine neoplasia type 2b (MEN 2b) is a rare genetic disorder. Affected individuals have malignant thyroid tumors, pheochromocytoma, and ganglioneuromatosis. The musculoskeletal manifestations of MEN 2b include a Marfanoid habitus, pes cavus, scoliosis, slipped capital femoral epiphysis, joint laxity, poor muscle development, and delayed maturation. The initial clinical presentation of MEN 2b frequently involves the musculoskeletal system. The characteristics ganglioneuromatosis of the lips and tongue, however, should alert the orthopedic surgeon to the underlying disorder. Effective treatment of the malignant neoplasms hinges on early diagnosis. The risk of perioperative hypertensive crisis is significant; it may be prevented by appropriate treatment of the pheochromocytoma.

Adolescent↗
PubMed1995

Multiple endocrine neoplasia 2B (MEN 2B)/MEN 3.

Multiple endocrine neoplasia type 2B/3 is characterized by multiple mucosal neuromas, a marfanoid appearance, medullary thyroid carcinoma, pheochromocytoma, gastrointestinal ganglioneuromatosis, and thickened corneal nerves. This rare syndrome is inherited in an autosomal dominant pattern. Early recognition followed by appropriate screening and treatment can be life-saving.

Adrenal Gland Neoplasms↗
PubMed1995

The RET proto-oncogene and cancer.

The RET proto-oncogene, a receptor tyrosine kinase, has been evaluated as a candidate gene for multiple endocrine neoplasia type 2A and type 2B (MEN 2A and MEN 2B), for familial medullary thyroid carcinoma (FMTC), and for sporadic cases of medullary thyroid carcinoma (MTC) and pheochromocytomas. We determined the genomic structure of RET and used single-strand conformational polymorphism (SSCP) analysis to identify sequence variants in genomic DNA from families segregating MEN 2 and FMTC. In addition, we examined paired tumour and lymphocyte genomic DNAs from individuals with sporadic cases of MTC and pheochromocytoma. Altogether, we and others found 21 missense mutations in five cysteines clustered in the extra-cellular domain of RET (exons 10 and 11) associated with 111 MEN 2A and FMTC families. In contrast, a single point mutation that results in the substitution of threonine for methionine within the catalytic core of the tyrosine kinase domain (codon 918, exon 16) is responsible for all 66 reported cases of MEN 2B. Two missense mutations and a six base-pair deletion were identified in MTC tumour DNA, but no mutations were identified from pheochromocytoma tumour DNAs. A predictive DNA test for MEN 2A-associated mutations in RET has been developed that is based on detection of missense mutations by polymerase chain reaction (PCR) amplification and restriction endonuclease cleavage. A dominant oncogene model for the action of the RET gene product is proposed as a mechanism of action in MEN 2A, MEN 2B, FMTC and for at least some cases of sporadic MTC.

Adrenal Gland Neoplasms↗
PubMed1995

[The direct gene test in familial medullary thyroid gland carcinoma and in MEN syndromes. Detection of mutations in the ret proto-oncogene saves screening studies].

Multiple endocrine neoplasias, type 2A and type 2B (MEN2A, MEN2B), and familial medullary thyroid carcinoma (FMTC) have an autosomal dominant mode of inheritance. The risk of passing on the disease is almost 50%. Early diagnosis and surgical intervention largely prevents aggressive metastasis of thyroid carcinoma, the main cause of death. The diagnostic possibilities have been much improved by the implementation of direct gene testing. Exclusion of the inheritance of a parental mutation in the RET proto-oncogene removes the potential risk of progeny contracting the disease, and obviates the need for the usual annual screening from age 5 years onward. In many of those cases in whom a mutation is detected, prophylactic surgical intervention should be considered.

Adolescent↗
PubMed2004

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.

Adult↗
PubMed1996

A potential pathogenetic mechanism for multiple endocrine neoplasia type 2 syndromes involves ret-induced impairment of terminal differentiation of neuroepithelial cells.

Germ-line missense mutations of the receptor-like tyrosine kinase ret are the causative genetic event of the multiple endocrine neoplasia (MEN) type 2A and type 2B syndromes and of the familial medullary thyroid carcinoma. We have used the rat pheochromocytoma cell line, PC12, as a model system to investigate the mechanism or mechanisms by which expression of activated ret alleles contributes to the neoplastic phenotype in neuroendocrine cells. Here we show that stable expression of ret mutants (MEN2A and MEN2B alleles) in PC12 cells causes a dramatic conversion from a round to a flat morphology, accompanied by the induction of genes belonging to the early as well as the delayed response to nerve growth factor. However, in the transfected PC12 cells, the continuous expression of neuronal specific genes is not associated with the suppression of cell proliferation. Furthermore, expression of ret mutants renders PC12 cells unresponsive to nerve growth factor-induced inhibition of proliferation. These results suggest that induction of an aberrant pattern of differentiation, accompanied by unresponsiveness to growth-inhibitory physiological signals, may be part of the mechanism of action of activated ret alleles in the pathogenesis of neuroendocrine tumors associated with MEN2 syndromes.

Adrenal Gland Neoplasms↗
PubMed1995

Rudolf-Virchow-Preis 1995. The role of RET proto-oncogene mutation analysis in the diagnosis of multiple endocrine neoplasia type 2 (MEN 2) gene carriers and in the discrimination of sporadic and familial medullary thyroid carcinomas and pheochromocytomas.

The RET proto-oncogene codes for a receptor-type tyrosine-kinase with to date unknown ligand. Recently, germline point-mutations in RET cysteine codons of the extracellular cysteine-rich domain (encoded by exons 10 and 11) and in the tyrosine-kinase domain (encoded by exon 16) at codon 918, have been associated with the syndromes of multiple endocrine neoplasia (MEN) type 2A, MEN type 2B and familial medullary thyroid carcinoma (FMTC). In our recent studies we have analyzed tumor and germline DNA extracted from formalin-fixed and paraffin-embedded specimens of 45 patients and additional blood samples of 38 possible MEN 2 gene carriers for the presence of RET point mutations in exons 10 and 11 by non-radioactive single strand conformation polymorphism analysis (PCR-SSCP) and for exon 16 by heteroduplex gel electrophoresis. Mutational analysis was performed by fluorescence-based dideoxy terminator cycle sequencing of PCR-products with an automated DNA sequencer. Materials included 19 patients with MEN 2A associated tumors (13 medullary thyroid carcinomas, 6 pheochromocytomas), 3 patients with MEN 2B associated medullary thyroid carcinomas and 23 patients with clinically sporadic tumors (16 medullary thyroid carcinomas, 7 phenochromocytomas). In all 19 MEN 2A patients we found RET germline point-mutations either at cysteine codons 634 (14), 630 (1) in exon 11 or at codon 618 (4) in exon 10. All 3 MEN 2B patients demonstrated germline point mutations at codon 918 (Met-->Thr) in exon 16. In 2 patients with clinically sporadic medullary thyroid carcinomas we found a point mutation at codon 634 both in DNA of the tumor and normal tissue, indicating the presence of a de novo germline mutation. In 5 sporadic medullary thyroid carcinomas and 2 pheochromocytomas we found a somatic point mutations were identified in 11 patients. Our results indicate that mutational analysis of the RET proto-oncogene is not only suitable to identify and subtype MEN 2 gene carriers using blood DNA but also to distinguish sporadic from inherited medullary thyroid carcinomas and phenochromocytomas analyzing DNA extracted from archival tissue specimens.

Adrenal Gland Neoplasms↗
PubMed1998

Molecular mechanisms of development of multiple endocrine neoplasia 2 by RET mutations.

Biological and biochemical effects of multiple endocrine neoplasia type 2A (MEN-2A), type 2B (MEN-2B) and familial medullary thyroid carcinoma (FMTC) mutations on Ret function were investigated by transfection of NIH 3T3 cells. All mutations examined conferred transforming activity on Ret at variable levels. Cysteine mutations detected in MEN-2A and FMTC induced disulphide-linked homodimers of Ret on the cell surface, leading to activation of its intrinsic tyrosine kinase. Of these cysteine-mutated proteins, Ret with a codon 634 mutation had the highest transforming activity. The activity of Ret with a codon 609, 611, 618 or 620 mutation was approximately three- to five-fold lower than that of Ret with a codon 634 mutation. The first four mutations impaired the Ret cell surface expression or its correct maturation, resulting in the low transforming activity. On the other hand, the MEN-2B mutation appeared to activate Ret by an intramolecular mechanism without dimerization. In addition, we investigated the role of tyrosines present in the intracellular domain for the transforming activity of the mutant Ret proteins. As a result, we found that tyrosine 905 is essential for the transforming activity of the MEN-2A-Ret mutant protein whereas tyrosines 864 and 952 are critical for that of the MEN-2B-Ret mutant protein. Moreover, it turned out that tyrosine 1062 regulates the activity of both MEN-2A-Ret and MEN-2B-Ret and represents a binding site for the Shc adaptor protein.

Carcinoma, Medullary↗
PubMed1997

The molecular genetics of multiple endocrine neoplasia type 2A and related syndromes.

Identification of RET gene mutations in patients at-risk for the development of the hereditary forms of medullary thyroid carcinoma has simplified management and expanded the scope of indications for surgical intervention. Patients who carry this mutation can be offered thyroidectomy at a very young age, hopefully at a point when the cancer has not yet developed or spread. Those who are found not to have inherited the mutation are spared further genetic and biochemical screening. This achievement marks a new paradigm in surgery--the recommendation that an operation be performed based on the result of a genetic test. Experience with management of patients with multiple endocrine neoplasia types 2A and 2B and with familial, non-multiple endocrine neoplasia medullary thyroid carcinoma will provide information that will aid in the future management of patients with other hereditary cancers.

Carcinoma, Medullary↗
PubMed2000

Medullary thyroid carcinoma in Northern Ireland, 1967-1997.

BACKGROUND: The experience of managing medullary thyroid carcinoma (MTC) in a specialist endocrine surgery unit was reviewed. METHODS: The case records of 38 patients (19 male, 19 female) treated over a 30 year period were studied. RESULTS: There were 23 (60.5%) patients with sporadic MTC while the remainder had familial MTC--12 multiple endocrine neoplasia (MEN) type 2A, two MEN type 2B, one non-MEN familial medullary thyroid carcinoma (FMTC). Sporadic MTC patients were significantly older at presentation (median 56 years, interquartile range 41.5-61.3 years) compared to MEN 2A patients (median 26 years interquartile range 17.5-34 years) and had more advanced stage of disease. Survival of MTC patients was significantly worse in sporadic disease than in those with MEN 2A (P < 0.0001). All familial cases had bilateral multifocal tumour whereas in sporadic patients only unilateral disease was seen. The availability of genetic testing now allows early identification of affected members of familial MTC kindreds. This has led to total thyroidectomy being performed on the basis of positive genetic screening alone in three patients (two MEN 2A, one FMTC), in all of whom widespread C-cell hyperplasia and microscopic multifocal invasive MTC were identified histologically. CONCLUSIONS: The management of MTC has changed during the study period with total thyroidectomy recommended as the primary procedure of choice for all patients. In the familial setting, positive genetic testing now allows thyroidectomy to be performed at an early pre-clinical stage, with the hope of permanent cure.

Adolescent↗
PubMed2006

Multiple cutaneous neuromas and macular amyloidosis associated with medullary thyroid carcinoma.

Multiple cutaneous neuromas are rarely seen in dermatology practice. We report a case of multiple cutaneous neuromas, macular amyloidosis (MA), and medullary thyroid carcinoma (MTC) and discuss the interrelationship of the associated conditions. Multiple endocrine neoplasia 2 (MEN 2) is a hereditary syndrome that comprises MEN 2A, MEN 2B, and familial MTC. Germline mutations in the RET proto-oncogene is the underlying cause of the syndrome. MEN 2A and MEN 2B show some common endocrine manifestations including MTC and pheochromocytoma. There are reports of families with MA and MEN 2A. Multiple mucosal neuromas occur in 100% of patients with MEN 2B syndrome. Cutaneous neuromas are infrequently reported in MEN 2B syndrome. Our patient was a heterozygote carrier of GAG-->GAC mutation (Glu 768 Asp) in exon 13, codon 768 of the RET proto-oncogene. We speculate that our patient may represent an unusual presentation of MEN 2B or an overlap of MEN 2A and MEN 2B syndromes or a sporadic MTC case with unusual associations.

Amyloidosis↗
PubMed2002

Choroidal metastasis from medullary thyroid carcinoma in multiple endocrine neoplasia.

PURPOSE: To report choroidal metastasis from medullary thyroid carcinoma in a patient with multiple endocrine neoplasia (MEN) type 2b. DESIGN: Interventional case report. METHODS: Medullary thyroid carcinoma developed in a 20-year-old woman and led to the diagnosis of MEN 2b. She had mucosal neuromas on the lips and tongue and prominent corneal nerves in both eyes. Right choroidal metastasis developed when she was 36 years of age. RESULTS: The eye was treated with irradiation, but 9 months later the patient died of widespread metastases. CONCLUSIONS: In patients with MEN type 2b, choroidal metastasis can develop from medullary thyroid carcinoma. Although fundus abnormalities typically do not occur with MEN 2b, choroidal metastasis from medullary thyroid carcinoma is a potential fundus finding.

Adult↗
PubMed2005

[Multiple endocrine neoplasia syndromes. Type 2].

The second type of multiple endocrine neoplasia syndromes can be described as rare syndromes, heritable in autosomal dominant manner and linking medullary thyroid carcinoma to different tumors of endocrine organ system and endocrinopathies. This syndrome is divided into multiple endocrine neoplasia syndrome type 2A (MEN 2A), characterized with combination of medullary thyroid carcinoma, pheochromocytoma and primary hyperparathyroidism; type 2B (MEN 2B), characterized with combination of medullary thyroid carcinoma, pheochromocytoma, marfanoid habitus and ganglioneuromatosis, and familial medullary thyroid carcinoma syndrome, characterized with the only indication, which is hereditary medullary thyroid carcinoma. Though type 2 multiple endocrine neoplasia syndrome has been known since 1961, yet, the cause of the syndrome, which is germline mutations of c-ret protooncogene, was detected just a decade ago and syndrome pathogenesis with its characterized endocrine neoplasia carcinogenesis machinery were detected. Implementation of progressive genetic researches in clinical practice enabled precise diagnosis of multiple endocrine neoplasia syndrome and its subtypes not only for ill patients but also for healthy syndrome inheritors, e.g. relatives of the sick. Stated genotype link to phenotype helps to prognosticate possible combinations of endocrine neoplasia and endocrinopathies, and to choose purposeful patient observation. Genetic screening of the inheritors of multiple endocrine neoplasia type 2 syndrome enabled purposeful researches and observations of patients with a huge risk of uprising endocrine neoplasia, it also enabled application of effective prophylaxis methods, avoidance or early diagnostic of malignant tumors and life prognosis improvement for patients with malignant tumors while practicing well-timed treatment adaptation. This literature review contains the newest data on multiple endocrine neoplasia syndrome type 2 and its pathogenesis, diagnostics, patient observation, endocrine cancer prophylaxis and methods of treatment, which are characteristic for syndrome and which are being chosen according to biochemical endocrine neoplasia symptoms and genetic diagnosis.

Adolescent↗
PubMed2003

Oral manifestations of genodermatoses.

Many genodermatoses have distinct oral features that may help identify or confirm a genetic diagnosis. Oral features of the disorders described here are summarized in Table 1. These conditions provide clear examples of rapid progress in the field of genetic technology relevant to patient care. Less than a decade ago, the exact genetic locus of most of these disorders was unknown. Today, for many of these disorders, the exact location of the disease-causing mutation is known and clinical genetic testing is available for patients. This information has impact not only for genetic counseling and anticipatory medical care, but also provides insight into the mechanisms of disease. How this rapid progress will impact care, and ultimately treatment of patients, remains to be seen.

Ectodermal Dysplasia↗