[Clinical characteristics of multiple endocrine neoplasia]. / Séance dédiée aux tumeurs endocrines. Néoplasies endocriniennes multiples, aspects cliniques.

Multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2) are autosomal dominant inherited multiglandular diseases with familial and individual age-related penetrance and variable expression. The most frequent endocrine features of MEN1 are parathyroid involvement (> 95%), duodeno-pancreatic endocrine tissue involvement (80%), pituitary adenoma (30%), and adrenal cortex tumors (25%), with no clear syndromic variants. Identification of the germline MEN1 mutation confirms the diagnosis, but there is no phenotype-genotype correlation. All patients with MEN2 have medullary thyroid carcinoma (MTC). The most distinctive MEN2 variants are MEN2A (MTC+pheochromocytoma+hyperparathyroidism), MEN2B (MTC+pheo), and isolated familial MTC (FMTC). The prognosis of MEN2 is linked to the progression of MTC, which depends mainly on the stage at diagnosis and the quality of initial surgical treatment. This emphasizes the need for early diagnosis and management. The specific RET codon mutation correlates with the MEN2 syndromic variant and with the age of onset and aggressiveness of MTC. Consequently, RET mutational status should guide major management decisions, such as whether and when to perform thyroidectomy.

Pancreatic cancer and the FAMMM syndrome.

Hereditary cancer syndromes provide excellent models for molecular genetic studies that may aid significantly in case detection, surveillance, and management. Ultimately, molecularly based designer pharmaceuticals may emerge from this research, such as the case of trastuzumab (Herceptin) in HER-2/neu positive breast cancer, and imatinib (Gleevec) in chronic myelocytic leukemia and gastrointestinal stromal tumors. Importantly, these molecular findings may fuel significant clues to cancer control. This background is mentioned since surveillance and management of pancreatic cancer, a major concern of this manuscript, has been uniformly unsuccessful as evidenced by the close correspondence between its incidence and its mortality. Yet knowledge about its genetic and molecular pathology will hopefully ameliorate this vexing problem. One molecular genetic clue is the recently identified palladin mutation in two pancreatic cancer prone families. However, caution must be used toward the palladin mutation, as several recent publications have questioned its significance as a pancreatic cancer causing mutation. We provide a concise description of pancreatic cancer in concert with malignant melanoma in the familial atypical multiple mole melanoma (FAMMM) syndrome as a potential preventive model. This knowledge should help clinicians and basic scientists seize on the opportunity to develop more sensitive and specific screening and management programs in this disease; while a relatively small subset of pancreatic cancer may be readily identifiable through its FAMMM phenotype, coupled with its CDKN2A mutation, this hereditary disorder, given a keen knowledge of its natural history and molecular genetics, may prove to be an effective clinical preventive model.

Neoplasia endocrina múltiple tipo 2: un ejemplo para la prevención del cáncer / Multiple endocrine neoplasia type 2: a model for cancer prevention

La Neoplasia endocrina múltiple tipo 2 es un síndrome caracterizado por carcinoma medular de tiroides y feocromocitomas. La identificación de mutaciones del proto-oncogén RET como responsables de este síndrome ha brindado un método preciso para la identificación de los individuos susceptibles de desarrollar esta enfermedad. Además, la identificación de estas mutaciones ha permitido caracterizar la expresión clínica y la gravedad del carcinoma medular de tiroides, su tratamiento preventivo y su seguimiento. Esta revisión presenta una discusión concisa sobre el uso de la evaluación genética en el manejo del carcinoma medular de tiroides hereditario con énfasis en la intervención primaria para prevenir la mortalidad y la morbilidad asociadas con esta enfermedad.

From genes to decisions: evolving views of genotype-based management in MEN 2.

Diagnosis and management of MEN 2 has evolved considerably since the identification of the underlying disease mutations in the RETproto-oncogene. Presymptomatic detection and prophylactic surgical intervention are now the accepted standard of care. The strong correlation of disease phenotype and mutation genotype has already also allowed us to develop mutation-guided management strategies to optimize time ot intervention and schedule follow-up and management. As our understanding of the depth of these correlations increases we look forward to better refining our management regimes to fit both the best care requirements and the quality of life needs of the MEN 2 patient.

RB-mediated suppression of spontaneous multiple neuroendocrine neoplasia and lung metastases in Rb+/- mice.

Alterations in pathways mediated by retinoblastoma susceptibility gene (RB) product are among the most common in human cancer. Mice with a single copy of the Rb gene are shown to develop a syndrome of multiple neuroendocrine neoplasia. The earliest Rb-deficient atypical cells were identified in the intermediate and anterior lobes of the pituitary, the thyroid and parathyroid glands, and the adrenal medulla within the first 3 months of postnatal development. These cells form gross tumors with various degrees of malignancy by postnatal day 350. By age of 380 days, 84% of Rb+/- mice exhibited lung metastases from C-cell thyroid carcinomas. Expression of a human RB transgene in the Rb+/- mice suppressed carcinogenesis in all tissues studied. Of particular clinical relevance, the frequency of lung metastases also was reduced to 12% in Rb+/- mice by repeated i.v. administration of lipid-entrapped, polycation-condensed RB complementary DNA. Thus, in spite of long latency periods during which secondary alterations can accumulate, the initial loss of Rb function remains essential for tumor progression in multiple types of neuroendocrine cells. Restoration of RB function in humans may prove an effective general approach to the treatment of RB-deficient disseminated tumors.

[Preventive thyroidectomy in hereditary medullary thyroid gland carcinoma]. / Die prophylaktische Thyreoidektomie beim hereditären medullären Schilddrüsenkarzinom.

Screening for hereditary medullary thyroid carcinoma (MTC) includes both calcitonin stimulation tests and DNA analysis. Positive results of these diagnostic procedures are indicators for the presence of neoplastic C-cell hyperplasia or an asymptomatic MTC. Thyroidectomy and lymphadenectomy of the first compartment are mandatory in both conditions even in young children.

Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A.

BACKGROUND: Missense germ-line mutations in the RET protooncogene are associated with multiple endocrine neoplasia type 2A (MEN 2A). Detection of these mutant alleles in kindred members predicts disease inheritance and provides the basis for preventative thyroidectomy. METHODS: A polymerase chain reaction (PCR)-based genetic test for the 19 known RET mutations was designed to study 132 members of 7 kindreds with MEN 2A. Haplotypes also were constructed using genetic markers flanking the MEN 2A locus. Plasma calcitonin (CT) concentrations were determined before and after provocative testing. RESULTS: Direct DNA testing and haplotype analysis showed that 21 of 58 kindred members at risk for disease had inherited a mutation in the RET protooncogene associated with MEN 2A. Plasma CT concentrations were elevated in 9 of the 21 family members, but were normal in 12. After genetic counseling, 13 of the 21 kindred members (6 with normal and seven with elevated plasma CT levels), consented to immediate thyroidectomy. In each patient, the resected thyroid gland showed C-cell hyperplasia with or without medullary thyroid carcinoma. There were no metastases to regional lymph nodes, and postoperative stimulated plasma CT levels were normal. CONCLUSION: The PCR-based direct DNA test for RET mutations is accurate, rapid, and reproducible. For all 132 individuals evaluated, the results of direct DNA analysis were consistent with haplotype studies. The direct test for mutations in the RET protooncogene is the preferred method for screening MEN 2A kindreds. In family members who have inherited a RET mutation, total thyroidectomy is indicated, regardless of the plasma CT values.

[Preventive total thyroidectomy in children with MEN IIa syndrome]. / Prophylaktische totale Thyreoidektomie bei Kindern mit MEN IIa-Syndrom.

Three children of MEN IIa-families underwent a prophylactic total thyroidectomy (at the age of 4, 7 and 8 years). Pathologic examination showed a bilateral C-cell-hyperplasia in each case. The annual follow-up of the physically and mentally well-developing children so far showed normal calcitonin provocative testing. Members of risk families should undergo a screening program as early as possible.

[Multiple endocrine neoplasia type 1. Digestive hormones in the screening]. / Néoplasie endocrinienne multiple de type 1. Hormones digestives dans le dépistage.

Detection of subjects from a multiple endocrine neoplasia type 1 family must rest on clinical, biochemical and radiological data, since study of the genome is unable to detect these subjects. In the new family described here, 6 out of the 14 subjects explored were affected. One had a confirmed pancreatic endocrine tumour and in 3 others a pancreatic endocrine tumour was highly probable, since insulin and glucagon levels, as well as ultrasonic exploration of the pancreas were pathological. Measurements of gastrointestinal hormones gave normal results in all cases. We conclude that to detect this endocrine neoplasia in subjects at risk it seems necessary to measure plasma insulin levels and perform an abdominal ultrasonography.

The role of genetic screening in the management of hereditary malignancy.

The identification of closely linked markers for several genetic syndromes has resulted in the routine identification of gene carriers for these disorders before the development of disease manifestations. The experiences with the multiple endocrine neoplasia syndromes, multiple endocrine neoplasia type 2 in particular, provide one example of how genetic testing can be combined with ongoing screening, treatment and support mechanisms to help families cope with the treatment realities and the psychosocial aspects of genetic disease.

Screening and surgical intervention in the multiple endocrine neoplasia patient.

Persons with multiple endocrine neoplasias (MEN) are a unique group of patients that present with various APUDomas. Screening of family members can lead to early detection of these tumors and possible cure of potentially fatal tumors. Screening for the MEN syndromes at present is limited to provocative and biochemical parameters. The gene(s) responsible for these syndromes have not, as of yet, been characterized but in the future will add greatly to the ability to identify these patients early. Early surgical intervention of these APUDomas, has lead to an improved prognosis for these tumors. The screening and the surgical approach to each syndrome are outlined.

Prediction of affected MEN2A gene carriers by DNA linkage analysis for early total thyroidectomy: a progress in clinical screening program for children with hereditary cancer syndrome.

The gene predisposing to multiple endocrine neoplasia type 2A (MEN 2A) has been assigned to chromosome 10, and affected gene carriers can be identified before the development of associated malignancy in some informative families. We applied these advances in gene mapping to clinical screening for possible pediatric surgery. A family with MEN 2A, consisting of 88 members and their spouses, was studied to test the reliability of the provocation of plasma calcitonin with pentagastrin and the possibility of DNA diagnosis of mutated gene carriers with DNA probes closely linked to the MEN2A gene including RBP3 and FNRB genes. Nineteen of the 88 were diagnosed as MEN 2A carriers. Twelve of them were treated surgically and the others died of medullay thyroid carcinoma (MTC) or pheochromocytoma. A strikingly sensitive response of calcitonin was observed in all those with MTC. The genotypes cosegregating with the abnormal allele at MEN2A in this family could be deduced from clinically established affected members. The early detection of gene carriers allows us to concentrate our screening efforts on children at high risk and to release non gene carriers from repeated unnecessary testing. MEN2A is one of the first cancer syndromes for which DNA screening permits early detection of members at high risk.

[Prevention of familial tumor diseases using genetic counseling and early diagnosis]. / Prävention familiärer Tumorkrankheiten durch genetische Beratung und Frühdiagnostik.

Several types of familial cancer can be prevented from progressing into an advanced stage through genetic counselling and regular medical control of persons at risk. Measures of secondary cancer prevention and their efficacy are described for retinoblastoma, MEN2 syndrome, familial colorectal carcinoma with (FAP) or without (HNPCC) pre-existing polyposis coli, dysplastic naevi syndrome, basal cell naevi syndrome and von Hippel-Lindau syndrome. The prevention of malignancies is promising primarily for the familial forms, since persons at risk are motivated to employ preventive measures, especially if they can be identified through DNA diagnosis and counselled with concrete information. The establishment of familial cancer registries should be considered which improve the continuous medical care for all family members, even in the case of a change of the family physician or a loss of contact.

Screening of families predisposed to cancer development in The Netherlands.

Screening for hereditary tumours provides a basis for secondary prevention. In 1985, the Foundation for the Detection of Hereditary Tumours was established in The Netherlands to coordinate screening in families with hereditary tumours. In the initial period of four years a large number of families were collected. Registration started with families with the multiple endocrine neoplasia syndrome type 2 and familial adenomatous polyposis. Later, families with the familial dysplastic nevus syndrome, hereditary nonpolyposis colorectal cancer and the multiple endocrine neoplasia syndrome type 1 were also collected and inventoried, because expansion of the registry to include these syndromes was considered. As a general conclusion based on our studies, it may be said that screening of families with the multiple endocrine neoplasia syndrome type 2, familial adenomatous polyposis, familial dysplastic nevus syndrome, and hereditary nonpolyposis colorectal cancer leads to detection of these tumours in an earlier stage, which in turn may permit curative treatment and improvement of the prognosis and life expectancy. Screening of the MEN-1 syndrome may improve the prognosis by favouring appropriate management decisions. It is evident that a detailed family cancer history is extremely important as an indicator of a genetic basis and has implications for family screening and follow up. The doctor's task of ensuring that the necessary investigations are carried out is made easier by use of the facilities of the Foundation for the Detection of Hereditary Tumours. The registration system in particular has assured the continuation of periodic examination, because the specialist is kept informed at all times. The collection of data and the preparation of an inventory of the data of families with hereditary tumours on a national scale have contributed to both the understanding of these syndromes and the optimalization of the screening procedures. The study of hereditary tumours is important, because it can provide clues concerning carcinogenesis in general.