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Multiple endocrine neoplasia syndromes

The multiple endocrine neoplasia (MEN) syndromes are characterized by autosomal dominant inheritance with a high degree of penetrance but varying expression. This review gives a classification of these syndromes and a short summary of the historical background. The pathogenesis of the disease and its possible origin in the APUD cell system are discussed together with the mechanisms underlying normal and ectopic hormone production by MEN tumors on the basis of recent findings in molecular endocrinology. The natural history and the clinical manifestations of the different syndromes are described. The sensitivity and discriminative capacity of the tests used to detect the syndromes in an early stage are compared. The choice of therapy and criteria for the timing and extensiveness of treatment are also considered. Lastly, problems associated with the ethical and legal aspects of screening, central registration, and monitoring of relatives at risk are described.

Chronic overproduction of islet amyloid polypeptide/amylin in transgenic mice : lysosomal localization of human islet amyloid polypeptide and lack of marked hyperglycaemia or hyperinsulinaemia

SummaryType 2 (non-insulin-dependent) diabetes mellitus is characterised by hyperglycaemia, peripheral insulin resistance, impaired insulin secretion and pancreatic islet amyloid formation. The major constituent of islet amyloid is islet amyloid polypeptide (amylin). Islet amyloid polypeptide is synthesized by islet beta cells and co-secreted with insulin. The ability of islet amyloid polypeptide to form amyloid fibrils is related to its species-specific amino acid sequence. Islet amyloid associated with diabetes is only found in man, monkeys, cats and racoons. Pharmacological doses of islet amyloid polypeptide have been shown to inhibit insulin secretion as well as insulin action on peripheral tissues (insulin resistance). To examine the role of islet amyloid polypeptide in the pathogenesis of Type 2 diabetes, we have generated transgenic mice with the gene encoding either human islet amyloid polypeptide (which can form amyloid) or rat islet amyloid polypeptide, under control of an insulin promoter. Transgenic islet amyloid polypeptide mRNA was detected in the pancreas in all transgenic mice. Plasma islet amyloid polypeptide levels were significantly elevated (up to 15-fold) in three out of five transgenic lines, but elevated glucose levels, hyperinsulinaemia and obesity were not observed. This suggests that insulin resistance is not induced by chronic hypersecretion of islet amyloid polypeptide. Islet amyloid polypeptide immunoreactivity was localized to beta-cell secretory granules in all mice. Islet amyloid polypeptide immunoreactivity in beta-cell lysosomes was seen only in mice with the human islet amyloid polypeptide gene, as in human beta cells, and might represent an initial step in intracellular formation of amyloid fibrils. These transgenic mice provide a unique model with which to examine the physiological function of islet amyloid polypeptide and to study intracellular and extracellular handling of human islet amyloid polypeptide in pancreatic islets.

Detection of mRNA encoding calcitonin, calcitonin gene related peptide and proopiomelanocortin in human tumors

Expression of the calcitonin (CT)/calcitonin gene related peptide (CGRP) gene and the proopiomelanocortin (POMC) gene has been demonstrated by Northern blot hybridization analysis of RNA extracted from human medullary thyroid carcinoma (MTC), pheochromocytoma and lung carcinoma. CT mRNA in these tumors could not be distinguished in size from CT mRNA isolated from normal human thyroid tissue. CGRP mRNA (previously demonstrated in 12 out of 12 lung tumor cell lines investigated) could not be detected in 13 primary lung tumors or 10 metastases thereof. The length of POMC mRNA in MTCs (present in all 4 metastases investigated but not in 7 primary tumors) and pheochromocytomas is about 100 nucleotides more than pituitary POMC RNA. In lung tumors 2 POMC RNA species can be detected, one of the same size as in pituitary tissue and one about 100 nucleotides larger.

Evidence of multicentric origin of the multiple endocrine neoplasia syndrome type 2A (Sipple's syndrome) in a large family in the Netherlands: Diagnostic and therapeutic implications

Abstract The occurrence of simultaneous tumors in different organs and the multicentric localization of the tumors in each of these organs are discussed on the basis of the findings in six patients belonging to a large kindred with Sipples syndrome and in patients with Sipples syndrome not belonging to this kindred, as well as the data in the literature. The high number of accessory pheochromocytomas in this family and in the other patients with Sipples syndrome was striking. Both the pheochromocytomas and the accessories were found in the form of both cortical nodules and complete adrenal glands with hyperplastic medullary tissue. The invariable occurrence of pheochromocytoma changes in accessory adrenal tissue in this family and in other cases supports and demonstrates the multicentricity of tumor development in Sipples syndrome. The aim of surgical treatment should be to remove all the pheochromocytoma tissue identified in the adrenal glands, the celiac plexus and side chain regions, thereby reducing the chance of recurrence of the symptoms in these patients and the need for repeated surgical intervention. However, more extensive exploration of the chest, cervical area, etc., to attempt curative surgery, is too destructive to be justifiable. The medullary thyroid carcinoma, which is also multicentric in origin, is, on the contrary, a dangerous tumor for which total thyroidectomy with extensive neck exploration is obligatory, preferably in an early phase. A modified short calcium test which is especially sensitive in this early phase, is described for screening for medullary thyroid carcinoma.

Psychological risks of genetically testing children for a hereditary cancer syndrome

Parents in families with a hereditary cancer syndrome are often familiar with periodical clinical testing of both themselves and their children. Genetic testing is an additional early diagnostic option that is becoming available for an increasing number of hereditary cancer syndromes. Participants in genetic counseling programs for cancer syndromes are often parents who apply for their children. If a child is identified as a carrier of a specific disease-causing gene mutation, sometimes its parents must decide on when it will be treated can treatment be postponed until expression of the disease or should the child receive presymptomatic surgery? We discuss some of the possible risks of genetically testing children: distress as a result of ambivalent feelings towards testing, preoccupation with disease-related signs, changes in family interactions, the burdening prospect of a future disease and medicalization of the carrier-child.

Human Islet Amyloid Polypeptide Accumulates at Similar Sites in Islets of Transgenic Mice and Humans

The cellular mechanisms responsible for conversion of islet amyloid polypeptide (IAPP) into insoluble amyloid deposits in non-insulin-dependent diabetes mellitus (NIDDM) are not clear. Overexpression of IAPP and the amino acid sequence of human IAPP (hIAPP) have both been implicated. To examine factors involved in amyloid formation, transgenic mice expressing the hIAPP or rat IAPP (rIAPP) gene were generated. These mice had elevated plasma IAPP concentrations, and they were normoglycemic and normoinsulinemic. No amyloid deposits were detected by light microscopy. To examine the ultrastructure of islets, pancreatic tissue was studied from hIAPP and rIAPP transgenic mice and from age-matched control mice by immunoelectron microscopy. IAPP was immunolocalized in β-cell secretory granules of all mice, and the COOH- and NH2-terminal flanking peptides of hIAPP were localized in β-cell granules of hIAPP mice. Accumulations of nonfibrillar perivascular IAPP-immunoreactive material were found between capillaries and β-cells in hIAPP transgenic mice but not in rIAPP transgenic or control mice. Similar nonfibrillar masses were identified in islets of an NIDDM patient. Secondary lysosomes in β-cells and macrophages of hIAPP transgenic mice showed dense labeling for IAPP. We suggest that hIAPP is degraded more slowly than rIAPP or mouse IAPP by β-cell lysosomes. Accumulations of IAPP in islet perivascular spaces may represent the early stages of islet amyloid formation.

An improved method for the determination of islet amyloid polypeptide levels in plasma

We describe an improved method for the determination of islet amyloid polypeptide (IAPP) levels in plasma. Plasma is first extracted with acid-acetone, followed by a specific and sensitive radioimmunoassay (RIA) for IAPP using rabbit-anti-human-IAPP serum. Recovery of synthetic IAPP from plasma was 82±6% (n = 16). Standard samples, prepared in ‘hormone-free’ serum, were also extracted with acid-acetone. Displacement curves of serially diluted acid-acetone extracted plasma samples were parallel to the standard curve. The lower detection limit of the RIA was 2·3 ± 0·1 fmol/sample (n = 5). Intra-assay variations for IAPP concentrations of 4, 17 and 32 pM were 16·3% (n = 10), 9·2% (n = 10) and 6·2% (n = 10); inter-assay variations were 35·9% (n = 14), 19·9% (n = 15) and 15·4% (n = 15), respectively. Non-stimulated IAPP levels ranged from 2·4 to 12 pM (mean 6±4pM, n = 10) in healthy control subjects. IAPP was not detectable in type 1 (insulin-dependent) diabetic patients before and after glucagon administration. In type 2 (non-insulin-dependent) diabetic patients basal levels ranged from 2·2 to 14·5 pM and glucagon-stimulated levels ranged from 2·2 to 38·9 pM. The increase in IAPP varied from 0 to 24·4 pM. The anti-human-IAPP serum had full cross-reactivity with rat IAPP (= mouse IAPP). Transgenic mice overexpressing the human IAPP gene showed elevated plasma IAPP levels as compared to (non-transgenic) control mice. It is concluded that the method presented for the determination of IAPP in plasma is reliable and easy to perform, yielding reproducible results. The ability to measure plasma IAPP levels will help to elucidate the physiological function of IAPP as well as its pathophysiological role in type 2 diabetes mellitus.

Detection of circulating Tg-mRNA in the follow-up of papillary and follicular thyroid cancer: how useful is it?

To investigate the usefulness of thyroglobulin mRNA (Tg-mRNA) detection in peripheral blood in the follow-up of papillary and follicular (differentiated) thyroid cancer, a literature study was performed. Both evidence for and evidence against the usefulness of Tg-mRNA detection were found. Also, evidence for the expression of Tg-mRNA in cells other than normal or neoplastic thyroid follicular cells was found. It is concluded that currently Tg-mRNA detection is not a useful tool in the follow-up of differentiated thyroid carcinoma, but that the concept of using RT–PCR measurements during follow-up still warrants further research.

Acromegaly and hyperprolactinemia in a patient with polyostotic fibrous dysplasia : dynamic endocrine studies and treatment with the somatostatin analogue octreotide

Acromegaly and hyperprolactinemia have been described in association with polyostotic fibrous dysplasia; the pathogenetic mechanisms involved in the development of the endocrinopathies is unknown. We report a 26-year-old man with polyostotic fibrous dysplasia and hypersecretion of GH and PRL. Plasma GH, PRL, and insulin-like growth factor-l (IGF-I) were elevated. Glucose-non-suppressible plasma GH concentrations, GH responsiveness to TRH and GHRH, and GH suppression after a testdose of somatostatin, octreotide, and bromocriptine were found. Plasma GHRH levels were within the normal range (< 25 ng/l). Computed tomography of the sella turcica and visual fields were normal. [IIIln-DTPA-D-Phe’]-octreotide scintigraphy were used to localize a possible tumor; no radioactivity was visualized at the site of the hypothalamus, the pituitary or elsewhere in the body but a considerable accumulation of radioactivity was found in the os frontalis. Therapy with octreotide by continuos sc infusion partially suppressed GH and IGF-I (and normalized PRL). The results suggest that hypersecretion of GH in our patient is not due to a GH-secreting pituitary tumor, eutopic or ectopic hypersecretion of GHRH or autonomous somatotroph function. The origin of the disease in this patient might be an abnormal hypothalamic regulation of somatotrophs and/or an alteration in the transmembrane signalling systems.

Who Is at Risk for Psychological Distress in Genetic Testing Programs for Hereditary Cancer Disorders

Presymptomatic identification of disease gene carriers is becoming an increasingly common part of the clinical management of hereditary cancer disorders. With an expected increase in the number of requests for DNA testing and the limited resources for counseling, the amount of time genetic counselors are able to spend with test candidates will decrease. It is therefore important for counselors to identify persons at risk for psychological distress. Based on a review of experiences with Huntington disease and cancer patients, we describe factors likely to evoke distress in genetic cancer candidates. We also discuss the sometimes widely different ways that test candidates and their partners respond to genetic testing. By exploring risk factors for distress in relevant domains of the research, we can offer counselors guidelines for determining who may need extra counseling.