Clinical Screening as Compared with DNA Analysis in Families with Multiple Endocrine Neoplasia Type 2A
Multiple endocrine neoplasia type 2A (MEN-2A) is an inherited disease characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid adenoma 1 , 2 . MEN type 2B (MEN-2B) is characterized by medullary thyroid carcinoma, pheochromocytoma, mucosal ganglioneuroma, and a marfanoid habitu...
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| Published in | The New England journal of medicine Vol. 331; no. 13; pp. 828 - 835 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Boston, MA
Massachusetts Medical Society
29.09.1994
|
| Subjects | |
| Online Access | Get full text |
| ISSN | 0028-4793 1533-4406 |
| DOI | 10.1056/NEJM199409293311302 |
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| Abstract | Multiple endocrine neoplasia type 2A (MEN-2A) is an inherited disease characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid adenoma
1
,
2
. MEN type 2B (MEN-2B) is characterized by medullary thyroid carcinoma, pheochromocytoma, mucosal ganglioneuroma, and a marfanoid habitus
3
,
4
. In familial medullary thyroid carcinoma, medullary thyroid carcinoma occurs without the other abnormalities
5
–
7
. The pattern of inheritance of all these syndromes is autosomal dominant, with a high degree of penetrance and variable expression.
Medullary thyroid carcinoma originates in calcitonin-producing cells (C cells) of the thyroid gland
8
. Patients with this condition or its precursor, C-cell hyperplasia, have supranormal . . . |
|---|---|
| AbstractList | Multiple endocrine neoplasia type 2A (MEN-2A) is characterized by medullary thyroid carcinoma in combination with pheochromocytoma and sometimes parathyroid adenoma. Missense mutations in the RET proto-oncogene are associated with MEN-2A. Their detection by DNA analysis allows the identification of carriers of the gene, in whom the risk of medullary thyroid carcinoma is 100 percent. We compared the reliability of biochemical tests with that of DNA analysis in identifying carriers of the MEN2A gene.BACKGROUNDMultiple endocrine neoplasia type 2A (MEN-2A) is characterized by medullary thyroid carcinoma in combination with pheochromocytoma and sometimes parathyroid adenoma. Missense mutations in the RET proto-oncogene are associated with MEN-2A. Their detection by DNA analysis allows the identification of carriers of the gene, in whom the risk of medullary thyroid carcinoma is 100 percent. We compared the reliability of biochemical tests with that of DNA analysis in identifying carriers of the MEN2A gene.Starting in 1975, we screened 300 subjects in four large families with MEN-2A for expression of the disease, using measurements of plasma calcitonin after stimulation with pentagastrin or calcium and urinary excretion of catecholamines and catecholamine metabolites. We tested for carrier status by DNA analysis, including linkage analysis, and more recently by analysis of mutations in the RET gene.METHODSStarting in 1975, we screened 300 subjects in four large families with MEN-2A for expression of the disease, using measurements of plasma calcitonin after stimulation with pentagastrin or calcium and urinary excretion of catecholamines and catecholamine metabolites. We tested for carrier status by DNA analysis, including linkage analysis, and more recently by analysis of mutations in the RET gene.Of 80 MEN2A gene carriers (in 61 of whom carrier status was proved by DNA analysis), 66 had abnormal plasma calcitonin values and medullary thyroid carcinoma. Fourteen young carriers had normal results of plasma calcitonin tests. In 8 of these 14, thyroidectomy revealed small foci of medullary thyroid carcinoma; the remaining 6 have not yet been operated on. Of the other 220 family members, 68 were found by DNA analysis not to carry the MEN2A gene. None of these 68 subjects had medullary thyroid carcinoma or pheochromocytoma; 6 had elevated plasma calcitonin concentrations and underwent thyroidectomy but had only C-cell hyperplasia.RESULTSOf 80 MEN2A gene carriers (in 61 of whom carrier status was proved by DNA analysis), 66 had abnormal plasma calcitonin values and medullary thyroid carcinoma. Fourteen young carriers had normal results of plasma calcitonin tests. In 8 of these 14, thyroidectomy revealed small foci of medullary thyroid carcinoma; the remaining 6 have not yet been operated on. Of the other 220 family members, 68 were found by DNA analysis not to carry the MEN2A gene. None of these 68 subjects had medullary thyroid carcinoma or pheochromocytoma; 6 had elevated plasma calcitonin concentrations and underwent thyroidectomy but had only C-cell hyperplasia.Unlike biochemical tests, DNA analysis permits the unambiguous identification of MEN2A gene carriers.CONCLUSIONSUnlike biochemical tests, DNA analysis permits the unambiguous identification of MEN2A gene carriers. Background Multiple endocrine neoplasia type 2A (MEN-2A) is characterized by medullary thyroid carcinoma in combination with pheochromocytoma and sometimes parathyroid adenoma. Missense mutations in the RET proto-oncogene are associated with MEN-2A. Their detection by DNA analysis allows the identification of carriers of the gene, in whom the risk of medullary thyroid carcinoma is 100 percent. We compared the reliability of biochemical tests with that of DNA analysis in identifying carriers of the MEN2A gene. Methods Starting in 1975, we screened 300 subjects in four large families with MEN-2A for expression of the disease, using measurements of plasma calcitonin after stimulation with pentagastrin or calcium and urinary excretion of catecholamines and catecholamine metabolites. We tested for carrier status by DNA analysis, including linkage analysis, and more recently by analysis of mutations in the RET gene. Results Of 80 MEN2A gene carriers (in 61 of whom carrier status was proved by DNA analysis), 66 had abnormal plasma calcitonin values and medullary thyroid carcinoma. Fourteen young carriers had normal results of plasma calcitonin tests. In 8 of these 14, thyroidectomy revealed small foci of medullary thyroid carcinoma; the remaining 6 have not yet been operated on. Of the other 220 family members, 68 were found by DNA analysis not to carry the MEN2A gene. None of these 68 subjects had medullary thyroid carcinoma or pheochromocytoma; 6 had elevated plasma calcitonin concentrations and underwent thyroidectomy but had only C-cell hyperplasia. Conclusions Unlike biochemical tests, DNA analysis permits the unambiguous identification of MEN2A gene carriers. Multiple endocrine neoplasia type 2A (MEN-2A) is an inherited disease characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid adenoma 1 , 2 . MEN type 2B (MEN-2B) is characterized by medullary thyroid carcinoma, pheochromocytoma, mucosal ganglioneuroma, and a marfanoid habitus 3 , 4 . In familial medullary thyroid carcinoma, medullary thyroid carcinoma occurs without the other abnormalities 5 – 7 . The pattern of inheritance of all these syndromes is autosomal dominant, with a high degree of penetrance and variable expression. Medullary thyroid carcinoma originates in calcitonin-producing cells (C cells) of the thyroid gland 8 . Patients with this condition or its precursor, C-cell hyperplasia, have supranormal . . . Multiple endocrine neoplasia type 2A (MEN-2A) is characterized by medullary thyroid carcinoma in combination with pheochromocytoma and sometimes parathyroid adenoma. Missense mutations in the RET proto-oncogene are associated with MEN-2A. Their detection by DNA analysis allows the identification of carriers of the gene, in whom the risk of medullary thyroid carcinoma is 100 percent. We compared the reliability of biochemical tests with that of DNA analysis in identifying carriers of the MEN2A gene. Starting in 1975, we screened 300 subjects in four large families with MEN-2A for expression of the disease, using measurements of plasma calcitonin after stimulation with pentagastrin or calcium and urinary excretion of catecholamines and catecholamine metabolites. We tested for carrier status by DNA analysis, including linkage analysis, and more recently by analysis of mutations in the RET gene. Of 80 MEN2A gene carriers (in 61 of whom carrier status was proved by DNA analysis), 66 had abnormal plasma calcitonin values and medullary thyroid carcinoma. Fourteen young carriers had normal results of plasma calcitonin tests. In 8 of these 14, thyroidectomy revealed small foci of medullary thyroid carcinoma; the remaining 6 have not yet been operated on. Of the other 220 family members, 68 were found by DNA analysis not to carry the MEN2A gene. None of these 68 subjects had medullary thyroid carcinoma or pheochromocytoma; 6 had elevated plasma calcitonin concentrations and underwent thyroidectomy but had only C-cell hyperplasia. Unlike biochemical tests, DNA analysis permits the unambiguous identification of MEN2A gene carriers. |
| Author | Blijham, Geert van Veen, Joke M. Jansen-Schillhorn van Gils, Adriaan Landsvater, Rudy M Geerdink, Rolf A Beemer, Frits A Lips, Cornelis Jansen, Rumo van Vroonhoven, Theo de Wit, Mireille J van Amstel, Hans Kristian Ploos Berends, Marianne Brouwers-Smalbraak, Joanneke Hoppener, Jo Vroom, Thea M Zewald, Richard A |
| Author_xml | – sequence: 1 givenname: Cornelis surname: Lips fullname: Lips, Cornelis – sequence: 2 givenname: Rudy M surname: Landsvater fullname: Landsvater, Rudy M – sequence: 3 givenname: Jo surname: Hoppener fullname: Hoppener, Jo – sequence: 4 givenname: Rolf A surname: Geerdink fullname: Geerdink, Rolf A – sequence: 5 givenname: Geert surname: Blijham fullname: Blijham, Geert – sequence: 6 givenname: Joke M. Jansen-Schillhorn surname: van Veen fullname: van Veen, Joke M. Jansen-Schillhorn – sequence: 7 givenname: Adriaan surname: van Gils fullname: van Gils, Adriaan – sequence: 8 givenname: Mireille J surname: de Wit fullname: de Wit, Mireille J – sequence: 9 givenname: Richard A surname: Zewald fullname: Zewald, Richard A – sequence: 10 givenname: Marianne surname: Berends fullname: Berends, Marianne – sequence: 11 givenname: Frits A surname: Beemer fullname: Beemer, Frits A – sequence: 12 givenname: Joanneke surname: Brouwers-Smalbraak fullname: Brouwers-Smalbraak, Joanneke – sequence: 13 givenname: Rumo surname: Jansen fullname: Jansen, Rumo – sequence: 14 givenname: Hans Kristian Ploos surname: van Amstel fullname: van Amstel, Hans Kristian Ploos – sequence: 15 givenname: Theo surname: van Vroonhoven fullname: van Vroonhoven, Theo – sequence: 16 givenname: Thea M surname: Vroom fullname: Vroom, Thea M |
| BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=4232481$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/7915822$$D View this record in MEDLINE/PubMed |
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| CODEN | NEJMAG |
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| ContentType | Journal Article |
| Copyright | Copyright © 1994 Massachusetts Medical Society. All rights reserved. 1994 INIST-CNRS |
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| Keywords | Endocrinopathy Human Biochemical analysis Linkage Restriction fragment length polymorphism Family study Genetics Diagnosis Molecular biology Southern blotting Multiple endocrine neoplasia type II Comparative study |
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| References | Gibson WGH (r036) 1981; 75 Ponder BAJ (r029) 1989; 37 Iwamoto T (r019) 1993; 8 r020 Howe JR (r032) 1992; 51 Gibson WGH (r037) 1982; 106 r021 r022 r001 r017 r013 r014 r015 r016 Love DR (r033) 1993; 2 r038 Scopsi L (r039) 1991; 4 Kwok JBJ (r018) 1993; 8 r031 r010 r011 r012 Lips CJM (r025) 1987; 35 Jackson CE (r006) 1989; 37 van Gils APG (r023) 1991; 11 r030 DeGroot LJ (r035) 1975; 59 r028 r007 r008 r009 Landsvater RM (r026) 1993; 52 r002 r024 r003 r004 r005 r027 Love DR (r034) 1993; 2 7915823 - N Engl J Med. 1994 Sep 29;331(13):870-1 |
| References_xml | – ident: r017 doi: 10.1093/hmg/3.2.237 – ident: r010 doi: 10.1056/NEJM197111112852004 – volume: 37 start-page: 116 year: 1989 ident: r006 publication-title: Henry Ford Hosp Med J – volume: 106 start-page: 388 year: 1982 ident: r037 publication-title: Am J Pathol – ident: r004 doi: 10.1016/0030-4220(76)90187-0 – ident: r021 doi: 10.1016/0002-9343(78)90575-2 – ident: r022 doi: 10.1016/0002-9343(82)90710-0 – ident: r008 doi: 10.1056/NEJM197308302890901 – volume: 8 start-page: 2575 year: 1993 ident: r018 publication-title: Oncogene – ident: r020 doi: 10.1016/0002-9343(87)90641-3 – ident: r011 doi: 10.1056/NEJM198802253180804 – volume: 2 start-page: 491 year: 1993 ident: r034 publication-title: Hum Mol Genet – volume: 37 start-page: 205 year: 1989 ident: r029 publication-title: Henry Ford Hosp Med J – ident: r013 doi: 10.1038/328528a0 – ident: r009 doi: 10.1210/jcem-39-3-487 – ident: r014 doi: 10.1038/363458a0 – volume: 8 start-page: 1087 year: 1993 ident: r019 publication-title: Oncogene – ident: r007 doi: 10.1016/0888-7543(91)90237-9 – ident: r027 doi: 10.1007/BF00291386 – ident: r030 doi: 10.1093/nar/15.7.3196 – ident: r015 doi: 10.1093/hmg/2.7.851 – ident: r028 doi: 10.1016/0888-7543(88)90133-4 – ident: r016 doi: 10.1038/367375a0 – volume: 35 start-page: 133 year: 1987 ident: r025 publication-title: Henry Ford Hosp Med J – volume: 59 start-page: 1233 year: 1975 ident: r035 publication-title: Med Clin North Am doi: 10.1016/S0025-7125(16)31971-X – volume: 51 start-page: 1430 year: 1992 ident: r032 publication-title: Am J Hum Genet – ident: r005 doi: 10.1002/bjs.1800730411 – ident: r024 doi: 10.1016/S0300-595X(81)80027-8 – ident: r012 doi: 10.1038/328527a0 – ident: r003 doi: 10.1056/NEJM196807042790101 – ident: r038 doi: 10.1016/S0046-8177(85)80276-8 – ident: r031 doi: 10.1093/nar/16.1.374 – volume: 11 start-page: 37 year: 1991 ident: r023 publication-title: Radiographics doi: 10.1148/radiographics.11.1.1671719 – volume: 52 start-page: 335 year: 1993 ident: r026 publication-title: Am J Hum Genet – ident: r002 doi: 10.1097/00005792-196809000-00001 – volume: 75 start-page: 347 year: 1981 ident: r036 publication-title: Am J Clin Pathol doi: 10.1093/ajcp/75.3.347 – ident: r001 doi: 10.1016/0002-9343(61)90234-0 – volume: 4 start-page: 297 year: 1991 ident: r039 publication-title: Mod Pathol – volume: 2 start-page: 491 year: 1993 ident: r033 publication-title: Hum Mol Genet – reference: 7915823 - N Engl J Med. 1994 Sep 29;331(13):870-1 |
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| Snippet | Multiple endocrine neoplasia type 2A (MEN-2A) is an inherited disease characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid adenoma
1... Multiple endocrine neoplasia type 2A (MEN-2A) is characterized by medullary thyroid carcinoma in combination with pheochromocytoma and sometimes parathyroid... Background Multiple endocrine neoplasia type 2A (MEN-2A) is characterized by medullary thyroid carcinoma in combination with pheochromocytoma and sometimes... |
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| SubjectTerms | Abdomen Adenoma Adolescent Adrenal Gland Neoplasms - diagnosis Adrenal Gland Neoplasms - genetics Adult Antigens Base Sequence Biological and medical sciences Calcitonin Calcitonin - blood Calcium (urinary) Catecholamines Child Child, Preschool Deoxyribonucleic acid DNA DNA Mutational Analysis DNA Probes Endocrinopathies Excretion Families & family life Family medical history Female Genetic Carrier Screening - methods Genetic Linkage Genetic Markers Hospitals Humans Hyperplasia Internal medicine Linkage analysis Male Malignant tumors Mass Screening Medical sciences Medical screening MEN2A gene Metabolites Middle Aged Missense mutation Molecular Sequence Data Multiple endocrine neoplasia Multiple Endocrine Neoplasia - diagnosis Multiple Endocrine Neoplasia - genetics Multiple Endocrine Neoplasia - pathology Mutation Neuroendocrine tumors NMR Nuclear magnetic resonance Parathyroid Pathology Pedigree Pheochromocytoma Pheochromocytoma - diagnosis Pheochromocytoma - genetics Phosphatase Plasma Proto-Oncogenes Ret protein Rodents Therapy Thyroid cancer Thyroid carcinoma Thyroid gland Thyroid Neoplasms - diagnosis Thyroid Neoplasms - genetics Thyroid Neoplasms - pathology Thyroid. Thyroid axis (diseases) Thyroidectomy |
| Title | Clinical Screening as Compared with DNA Analysis in Families with Multiple Endocrine Neoplasia Type 2A |
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