A Japanese family of 87 members in five generations with multiple endocrine neoplasia type 2A (MEN 2A) is described regarding the utility of screening tests for early detection of medullary thyroid carcinoma and the potential for DNA diagnosis of MEN 2A gene carriers. The screening programs for family members in this series include measurements of plasma calcitonin concentrations after intravenous injection of pentagastrin (0.5 μg/kg/5 sec) and 24-hour urinary excretion of catecholamines. While 18 MEN 2A patients had been previously diagnosed, these screening programs revealed five additional patients with MEN 2A (aged 16, 19, 35, 37, and 57). Prediction of MEN 2A gene carriers by DNA analysis has been attempted but is not yet possible in this family

Iwai, Naomi

Kobayashi, Tetsuro

Sakai, Shin-ichiro

Shimotake, Takashi

Yanagihara, Jun

English

Henry Ford Health System Scholarly Commons

Henry Ford Hospital Medical Journal Volume 37 Number 3 Article 11 9-1989 Results of a Screening Program for Multiple Endocrine Neoplasia Type 2A: A Clinical Study of a Japanese Family Takashi Shimotake Naomi Iwai Jun Yanagihara Tetsuro Kobayashi Shin-ichiro Sakai Follow this and additional works at: https://scholarlycommons.henryford.com/hfhmedjournal  Part of the Life Sciences Commons, Medical Specialties Commons, and the Public Health Commons Recommended Citation Shimotake, Takashi; Iwai, Naomi; Yanagihara, Jun; Kobayashi, Tetsuro; and Sakai, Shin-ichiro (1989) "Results of a Screening Program for Multiple Endocrine Neoplasia Type 2A: A Clinical Study of a Japanese Family," Henry Ford Hospital Medical Journal : Vol. 37 : No. 3 , 124-126. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol37/iss3/11 This Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Henry Ford Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons. Results of a Screening Program for Multiple Endocrine Neoplasia Type 2A: A Clinical Study of a Japanese Family Takashi Shimotake,* Naomi Iwai,* Jun Yanagihara,* Tetsuro Kobayashi,* and Shin-ichiro Takai A Japanese family of 87 members in five generations wilh mulliple endocrine neoplasia type 2A (MEN 2A) is described regarding the utility of screening tests for early detection of medullary thyroid carcinoma andthe potential for DNA diagnosis of MEN 2 A gene carriers. The screening pro grams for family members in this series include measurements of plasma calcitonin concentrations after intravenous injection of pentagastrin (0.5 \i.glkgl5 sec) and 24-hour urinary excretion of catecholamines. While 18 MEN 2A patients had been previously diagnosed, these screening programs revealed five addilional patients with MEN 2A (aged 16, 19, 35, 37. and 57). Prediction of MEN 2A gene carriers by DNA analysis has been attempted bul is not yet possible in this family. (Henry Ford Ho.sp MedJ 1989;37:124-6) Mulfiple endocrine neoplasia type 2A (MEN 2A) is an auto-somal dominant syndrome characterized by the associa-tion of medullary thyroid carcinoma (MTC), pheochromocyto-ma, and hyperparathyroidism. A carrier of the MEN 2A gene often shows clinical signs or symptoms of these associated dis-eases, such as cervical nodes, hypertensive attacks, and re-peated severe headaches in the third or fourth decade of life (I), However, in the kindred at high risk for MEN 2A, early diag-nosis of MTC is possible even at an eariy stage, including "oc-cult disease," by measuring plasma calcitonin (CT) concentra-tions after intravenous injection of calcium or pentagastrin (2). tn recent years, prospective studies including children have been initiated in some insriturions, and many young parients with MEN 2A have been diagnosed and treated surgically (3-5). A Japanese family with MEN 2A was invesfigated regarding early diagnosis of MTC by screening tests in childhood and the possibility of DNA diagnosis of gene carriers. Patients and Methods The H-kindred is a Japanese family (cunently 87 members) with MEN 2A. Members of this family had many episodes of cervical tumors and often experienced characteristic attacks such as repeated headache, sweating, and pale face. Some un-derwent thyroidectomies and/or adrenalectomies. However, most of the family members had been reluctant to consult physi-cians because of the surgery required for relatives and the severe hypertensive attacks which were sometimes fatal. Patients were also anxious about violation of the individual privacy of un-affected relatives. For these reasons, no systematic investigation had been performed on this family. The clinical complaints of cervical nodule and repeated severe headache in a 34-year-old male in this family in 1987 provided us the opportunity to ap-proach this family. Screening program The medical history and cause of death of family members were investigated by interviewing their relatives or studying their medical records. The surviving pafients were interviewed and their medical records reviewed. Screening programs included biochemical measurements of specimens from the first- and second-degree relatives ofthe pa-tients. For detection of MTC, plasma CT concentrations were measured following provocative agents. CT was determined by radioimmunoassay on blood samples coUected before and at 2, 5, and 10 minutes following intravenous administration of pen-tagastrin (0.5 p.g/kg/5 sec). For detection of pheochromocyto-mas, 24-hour urine specimens were collected for an estimation of the excretion of epinephrine and norepinephrine. Genotype at RBP3 locus DNA was extracted from leukocytes or lymphobtastoid cell lines ofeach member of the family. Restriction fragment length polymorphisms (RFLPs) were determined using H.4IRBP, con-taining the 3' region of the cDNA of refinol binding protein 3 (6) as a probe after complete digesfion of DNA with Bglll. Submitted lor publication: September .TO. 1989. Accepted for publication: October 20. 1989. •Division of Surgery. Children's Research Hospital. Kyoto Prefectural University of Medicine. Kyoto, Japan. tSecond Department of Surgery, Osaka University Medical School, Osaka, Japan. Address correspondence to Dr Shimotake, Division of Surgery, Children's Research Hospital, Kyoto Prefectural University of Medicine, 465, Kawaramachi-Hirokoji, Ka-migyo-ku, Kyoto 602, Japan. 124 Henry Ford Hosp Med J—Vol 37. Nos 3 cSc 4, 1989 Clinical Study of a Japanese MEN 2A Family—Shimotake et al • ® M T C : n O P h o o ; • • M T C + Pheo B O SUSP Fig 1—Pedigree ofthe H-kindred. A crossbar through the indi-vidual symbol indicates the patient is deceased. MTC = medullary thyroid carcinoma, pheo = pheochromocytoma, SUSP = suspected MTC, .squares = males, circles = females. Results Eighteen patients with MEN 2A were confirmed by medical records or screening programs. This autosomal dominant syn-drome is inherited with high penetrance (Fig 1), Screening tests are continued yearly until the age of 40 for the relatives whose data were negative for MEN 2A. Results of screening program Twenty-six family members (aged 3 to 62) were screened for the progression of C-cell abnormalities and pheochromocyto-mas. Abnormal responses of CT levels were observed in six sub-jects (aged 16, 19, 33, 35, 37, and 57) (Fig 2). Five underwent total thyroidectomy with regional lymph node dissection soon after the screening test, and in each case multicentric growth of MTC was found. The remaining patient, a 33-year-old male, was not operated on because of a less sharp response compared with that of the others, but he has been followed carefully. The two youngest parients, a 16-year-old boy and his 19-year-oId sis-ter, underwent total thyroidectomy for bilateral MTC (the largest diameters; 16 mm and 3 mm in the boy; 14 mm and 7 mm in the giri). Small metastatic foci of MTC were found in the cervical lymph nodes of the t6-year-otd boy. The oldest pafient, a 57-year-old femate, had huge bilateral MTC. Her stimulated plasma CT level was more than 200,000 pg/mL (the normal up-per limit of plasma CT level in our series was 150 pg/mL). The 26 family members screened also had 24-hour urinary excretions of epinephrine and norepinephrine measured for de-tection of pheochromocytoma. Three of these subjects (aged 35, 37, and 57), who had been diagnosed as having MTC in the screening process, showed abnormal elevafions (Fig 3). Adrenal pheochromocytomas were detected upon further examination, and a right adrenalectomy, a left adrenalectomy, and a bilateral adrenalectomy were performed in the 35-year-oId, 37-year-old, and 57-year-otd patients, respectivety. Prediction of the gene carrier by RFLPs at the RBP3 locus Unfortunately, the RBP3 allele cosegregating with the dis-ease could not be detennined from the data obtained, and there-fore DNA diagnosis of gene carriers was not possible in this family using this particular probe. Henry Ford Hosp Med J—Vol 37. Nos 3 & 4. 1989 [pg/ml] < cc 10 5 . O 10* o o _J < CO < 10= 10^ 10 0 — I — 5 T 1 10 [min] Fig 2—Results of screening with the measurement of plasma calcitonin concentration following an intravenous injection of pentagastrin (0.5 \x.glkgl5 sec). Discussion Clinical screening programs for MEN 2A with stimulated plasma CT measurements have been utilized for early detection of MTC. The results of these screening programs have clarified the importance of early diagnosis of this hereditary malignant syndrome with the improvement of prognosis for affected pa-tients (7). Pediatric implications for MEN 2A have been discussed since the establishment of the value of measuring plasma CT for early diagnosis of MTC which has resulted in the inifiation of periodic screening tests for young family members. Gagel et at (4) re-ported the results of a prospective screening program for MEN 2A in which periodic tests had been inifiated at the age of 5. In their series hatf of the gene carriers were found before the age of 12, and in 80% of those patients the diagnosis of MEN 2A was made before the age of 20. Tetander et at (5) reported the results of totat thyroidectomy in 14 children with MEN 2A who were 12 years old or younger and recommended initiating the screening test at the age of t year and performing total thyroidectomy as soon as MTC or C-cetl hyperplasia was diagnosed. In our series, two of the 11 members aged 19 or younger who received screen-ing tests were diagnosed as having MEN 2A and were treated Clinical Study of a Japanese MEN 2A Family—Shimotake et al 125 [/^g/24hr] 50-4 0 2: X LU 30 20 10-200 [//g/24hr] NOREPINEPHRINE Fig 3—Results of screening with the measurement of 24-hour urinary excretion of epinephrine and norepinephrine. Pheo-chromocytoma was diagnosed in three members aged 35, 37, and 57. surgically. Surgery has shown MTC metastases to the cervical lymph nodes in a 16-year-otd mate. Therefore, despite the trou-blesome procedures and the emotional strain burdening at-risk infants and children who have no clinical complaints, these screening programs must be started in childhood for improve-ment of the prognosis in this syndrome. Recently the gene predisposing to MEN 2A was assigned to the pericentromeric region on chromosome 10 by the tight link-age with the RBP3 gene (8,9), and this linkage was confirmed in a Japanese family (10). DNA diagnosis may be possible in an informative family by determining genotypes at the RBP3 locus if the allele cosegregating with the disease can be determined. In our family, howeven it has not been possible because the af-fected parents were deceased or homozygous at the RBP3 locus with Bglll digestion. We are now trying other enzymes and other probes linked with MEN2A, and DNA diagnosis of gene carriers is expected to be possible in this family soon. The early detection of MEN 2A gene earners may prevent noncarriers of the MEN 2A gene from having periodic, trou-blesome screening tests. DNA can be obtained from peripheral blood samples at the initial screening test, from the umbilical cord blood samples at birth, or theoretically even from amniotic fluid or chorionic villus samples obtained before birth (11). What screening procedure is best within MEN 2A families? Perhaps screening programs should inctude DNA linkage anatysis for detection of MEN 2A gene carriers in addition to the conven-tional screening tests as more informative markers are obtained closer to and flanking the MEN 2A gene. Acknowledgment This work was partly supported by a Grant-in-Aid for Special Project Research, Cancer-Bioscience, from the Ministry of Edu-cation, Science and Culture of Japan. References 1. Telenius-Berg M. Berg B. Hamberger B, et al. Impact of screening on prognosis in Ihe multiple endocrine neoplasia type 2 syndromes: Natural history and treatment results in 105 patients. Henry Ford Hosp Med J 1984:32:225-32. 2. Wells SAJn Baylin SB, LeighlGS, Dale JK, Dilley WG, Famdon JR. The importance of early diagnosis in patients with hereditary medullary thyroid car-cinoma. Ann Surg 1982;195:595-9. 3. Leape LL, Miller HH, Graze K, et al. Total thyroidectomy for occult fa-milial medullary carcinoma of the thyroid in children. J Pediatr Surg 1976;11:831-7. 4. Gagel RF, Jackson CE, Block MA, et al. Age-related probability of devel-opment of hereditary medullary thyroid carcinoma. J Pediatr 1982;101:941-6. 5. Telander RL. Zimmerman D. van Heerden JA. Sizemore GW. Results of early thyroidectomy for medullary carcinoma in children with multiple endo-crine neoplasia type 2. J PediattSurg 1986:21:1190-4. 6. Liou GI, Wang C, Fong SL, et al. Bgl II recognized by a human IRBP cDNA localized to chromosome 10. Nucleic Acids Res 1987:15:3196. 7. Gagel RF, Tashjian AH Jn Cummings T, et al. The clinical outcome of pro-spective screening for multiple endocrine neoplasia type 2: An 18-year experi-ence. N Engl J Med 1988;318:478-84. 8. Mathew CGP, Chin KS, Easton DF, et al. A linked genetic marker for mul-tiple endocrine neoplasia type 2A on chromosome 10. Nature 1987;328:527-8. 9. Simpson NE, Kidd KK, Goodfellow PJ, et al. Assignment of multiple en-docrine neoplasia type 2A lo chromosome 10 by linkage. Nature 1987;328:528-30. 10. Yamamoto M. Takai S, Miki T, et al. Close linkage of MEN2A with RBP3 locus in Japanese kindreds. Hum Genet 1989:82:287-8. 11. Rhoads GG, Jackson LG, Schlesselman SE, et al. The safety and efficacy of chorionic villus sampling for early prenatal diagnosis of cytogenetic abnor-malities. N Engl J Med 1989;320:609-17. 126 Henry Ford Hosp Med J—Vol 37. Nos 3 & 4.1989 Clinical Study of a Japanese MEN 2A Family—Shimotake et al 

Results of a Screening Program for Multiple Endocrine Neoplasia Type 2A: A Clinical Study of a Japanese Family

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Results of a Screening Program for Multiple Endocrine Neoplasia Type 2A: A Clinical Study of a Japanese Family

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