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KISEP J Korean Neurosurg Soc 34 : 369-371, 2003

Case Report Familial Multiple Endocrine Neoplasia, Type I, in Identical Twins

Wee Hyun Kwon, M.D., Moo Seong Kim, M.D., Yong Tae Jung, M.D., Jae Hong Sim, M.D. Department of , Inje University, Busan Paik Hospital, Busan, Korea

We report of case of one monozygotic twin sister with pituitary tumor and multiple endocrine neoplasia, type 1.The older sister, 31-year-old woman, had undergone Gamma Knife radiosurgery for producing pituitary microadenoma. Four years later, pancreatic was detected, distal pancreatectomy and splenectomy were done. The younger sister, 31-year-old woman, had been operated for pancreatic insulinoma, 12 years ago. One year ago, hyperparathyroidism and pituitary macroadenoma were detected. Tumor removal was followed by Gamma Knife radiosurgery for residual tumor.

KEY WORDS : Monozygotic twin·Pituitary tumor·Pancreatic insulinoma·Hyperparathyroidism· Familial multiple type I.

Introduction Case Reports

ultiple endocrine neoplasia(MEN) is a disorder in Case 1 M which formation or hyperplasia affects The older 31-year-old woman showed elevated serum various endocrine . Multiple endocrine neoplasia type I prolactin concentration of 179ng/ml. Brain magnetic is called Wermer's syndrome and it is an autosomal dominant resonance imaging showed pituitary microadenoma. She disorder consisting of primary hyperparathyroidism as well as received gamma knife radiosurgery for the pituitary tumor pancreatic tumor and pituitary adenoma3). Less frequent with maximal dose 50Gy and marginal dose 25Gy on findings include adrenocortical tumors, tumors, February, 24, 1997(Fig. 1). She complained of hypoglyce- bronchial and intestinal tumors, and subcutaneous mia from July, 2000 ; abdominal computed tomograp- and visceral lipomas3). The genetic abnormality underlying hy(CT)(Feb-8-2001) showed mass in the pancreatic tail and MEN I has recently been located on chromosome 11. insulinoma was confirmed on pathologic examination(Fig. 2). Hyperparathyroidism is the most common manifestation of Distal pancreatectomy and splenectomy were undertaken on MEN I. Most patients can be identified by the age of 30 March 15, 2001. Follow-up brain magnetic resonance(MR) years. Pancreatic tumors may result in gastrin excess, image(June 13, 2001) revealed no mass and serum prolactin hyperinsulinemia, or excess production of vasoactive level was normalized to 24.02ng/ml. She had received 5 intestinal peptide1,4,5,9). At autopsy, is found cycles of and 5-FU chemotherapy. in 65% of patients with MEN I. The most common manife- stations of pituitary dysfunction are hyperprolacti-nemia, followed by and Cushing's disease2). The older 31-year-old sister had pancreatic insulinoma, hyperparathyr- oidism, pituitary macroadenoma, and the monozygotic twin 31-year-old younger sister had pituitary microadenoma, pancreatic insulinoma. A B C Received：May 19, 2003 Accepted：July 9, 2003 Fig. 1. Case 1. She had received Gamma knife radiosurgery for Address for reprints：Wee Hyun Kwon, M.D., Department of pituitary microadenoma(A). Four years later, magnetic resonance Neurosurgery, Inje University, Busan Paik Hospital, Busan 614-735, image showing no tumor(B). However, she complained hypoglyce- Korea mia and abdominal computed tomographic scan shows pancreatic Tel：051) 890-6144, Fax：051) 898-4244 insulinoma(C). She had been operated on pancreatectomy and E-mail : [email protected] splenectomy.

VOLUME 34 October, 2003 369 Familial Endocrine Neoplasia

Case 2 for residual tumor with maximal dose 20Gy and marginal Monozygotic twin dose 10Gy. of the case 1 underw- ent abdominal surge- Discussion ry for a pancreatic in- sulinoma on 1989, ultiple endocrine neoplasia caused hypersecretion of and neck surgery for M which manifestations of the multiple a hyper-parathyro- endocrine glands. Multiple endocrine neoplasia type I (MEN idism on May, 2001 Fig. 2. Case 1. Pathology showed insuli- type I, Wermer's syndrome) is concerned with tumor (Fig. 3). noma( tumor). Tumor trabecu- oncogene mutations of parathyroid, pituitary and pancreatic She complained of lae and microlobuli separated by islet cell. Involvement of pancreatic islet cells in MEN type I abundant hyalinized stroma(H&E×200). visual disturbance : varies in incidence from 30~80%. , , right eye vision, 1.2 ; VIPoma, , and -producing islet cell left eye vision, 0.15 ; tumors can occur3). There were four possible etiologies ; and the brain MR im- intrinsic factors, extrinsic factors, combination of intrinstic age revealed pituitary and extrinsic factors, and parathyroid mitogenic factor. macroadenoma(Fig. 4). Intrinsic factors consisted of neural crest hypothesis, Serum hormones were nesidioblastosis, chromosomal defects, oncogene activation. checked(prolactin : Neural crest hypothesis suggests that multiple endocrine 18.6ng/ml, GH : 2.25ng neoplasia syndromes might be attributable to some /ml, LH : 6.21 m/μ/ml, primordial, general defect in genetic or growth control of FSH : 6.23m/μ/ml, TSH : Fig. 3. Case 2. Pathology showed insuli- neural crest tissues. Nesidioblastosis attributed to the pancr- noma tumor cells an tumor cells are small 2.44m/μ/ml). and show indistinct nucleoli and fine eatic duct cell the primordial cell potential to regenerate acini, On August 31, 2001, chromatin(H&E×400). islets, and ducts through out life and pancreatic endocrine frontotemporal cran- tumor originate from immature precursor cells, not mature iotomy was performed to remove the tumor mass. On islet cells. It was thought MEN 1 genetic factor was tumor February 18, 2002, gamma knife radiosurgery was performed suppressor gene, location was chormosome 11. Extrinsic factors consisted of humoral secretogogues of abnormal growth of target endocrine cells, autoimmune mechanisms, growth factors involved in the etiology of parathyroid hyperplasia3). The origin of the growth factor hypothesis was unknown ; it was thought one of the fibroblast growth factor. Multiple endocrine neoplasia is autosomal dominant inheritance. There were following characteristics : First, the disease process within a single organ is multicentric ; second, A B hyperplasia is the initiating lesion, followed later by adenom- atous or carcinomatous changes ; third, neoplastic process in one endocrine organ affects the disease process in another organ. For example, production due to pancreatic tumor stimulates the pituitary tumor growth. Fourth, this syndrome happened for 30~40 years. Hyperpa- rathyroidism is the most common manifestation. Hypercalcemia may be present during the teenage years, C D and most individuals are affected by age 40. Calcium Fig. 4. Case 2. Younger sister had been operated for pancreatic excretion is usually elevated in the patient with MEN type 1 insulinoma(A,B). 13 years later, she complained visual disturbance. or other of primary hyperparathyroidism and low in familial Brain magnetic resonance image showed pituitary macroade- noma(C). She underwent operation for the tumor removal followed hypocalciuric hypercalcemia. In addition, serum calcium by Gamma knife radiosurgery(D). production was rarely elevated in MEN type 1 after birth, but

370 J Korean Neurosurg Soc 34 WH Kwon, et al. elevated in familial hypocalciuric hypercalcemia after birth. in 40% of the patients with macroadenoma. In acromegalic Neoplasia of the is the second most common patients who were treated surgically, 81% of those with manifestation of MEN I and tends to occur parallel with microadenoma and 68% of those with macroadenoma had hyperparathyroidism. The syndromes of pancreatic islet cell normal levels of GH postoperatively8). These are following hormone excess consist of increases in the level of pancreatic characteristics that pancreatic islet tumors in MEN have : 1. polypeptide(75~85%), gastrin(60%, Zollinger-Ellison First, the pancreatic islet cell tumors are multicentric ; syndrome), (25~35%), vasoactive intestinal malignant tumor occurs about a third of the time, and causes (VIP) (3~5%, Verner-Morrison syndrome), (5~10%), death in 10 to 20 percent of the patients. Second, removal of (1~5%). Zollinger-Ellison syndrome is caused by all pancreatic islets to prevent malignancy causes excessive gastrin production and occurs in more than half of mellitus, a disease with severe long-term complications. MEN I patients with pancreatic islet cell tumors. Clinical Management of metastatic islet cell is unsatisf- features include increased gastric acid production, recurrent actory. Hormonal abnormalities can sometimes be controlled. peptic ulers, and esophagitis. Insulinoma causes For example, Zollinger-Ellison syndrome can be treated with hypoglycemia in about one-third of MEN 1 patients with H2 receptor antagonists or omeprazole ; and the somatostatin pancreatic islet cell tumors. The tumors may be benign or analogue is useful in the management of carcinoid malignant(25%). On occasion, the diagnosis can be establis- and the watery diarrhea syndrome. Bilateral adrenalectomy hed by documenting hypoglycemia during a short fast with may be required for ectopic ACTH syndrome if medical simultaneous inappropriate elevation of serum insulin and C- therapy is ineffective. peptide levels. More commonly, it is necessary to subject the patient to a supervised 72-hour fast to provoke hypoglycemia. Conclusion Pituitary tumor is seen in 70~80% of the multiple endocrine neoplasia, type I. Of these tumors, are the most amilial multiple endocrine neoplasia is very rare. MEN common, followed by excessive production of GH and non- F type I is consists of pituitary tumor, pancreatic tumor, functioning tumor8). The frequency of microadenomas in the hyperparathyroidism. We reported familial MEN type 1 in present study was greater than that in earlier reports. In the monozygotic twin with literature review. Pituitary disease is past, pituitary macroadenoma was 73%, but now it was frequently and initial manifestation of MEN 1. If the pituitary decreased to 44%, due to MRI image technique development. tumor patient complains of hypoglycemia, study for multiple Also of note is that 75% of the women with had endocrine neoplasia, type 1, should be performed. microadenoma whereas only 42% of the men did8). Scheithauer et al.6), mentioned 33 of the 34 cases were References adenoma, 1 case mixed adenoma and hyperplasia in an 1. Ballard HS, Frame B, Hartsock RJ : Familial multiple endocrine histopathology and immunophenotypical study. In Timothy, adenoma-peptic ulcer complex. Medicine (Baltimore) 43 : 481-516, 1964 8) et al study , 43% of the operated on 30 patients showed 2. Bone HG II : Diagnosis of the multiglandular endocrine neoplasias. immunopositive for multiple hormone. Clin Chem 36 : 711-718, 1990 3. Brandi ML, Marx SJ, Aurbach GD, Fitzpatrick LA : Familial There was no treatment difference between MEN and non- multiple endocrine neoplasia Type I : A new look at pathophysio- MEN. 71.2% of the pituitary microadenona, 31.8% of the logy. Endocr Rev 8 : 391-405, 1987 pituitary macroadenoma showed normalized prolactin level 4. Hershon KS, Kelly WA, Shaw CM, Schwartz R, Bierman EL : Prolactinomas as part of the multiple endocrine neoplastic syndrome 8) after operation. Timothy et al. mentioned 88% of the Type 1. Am J Med 74 : 713-720, 1983 patients who had prolactionoma caused by microadenoma 5. Oberg K, Skogseid B, Eriksson B : Multiple endocrine neoplasia Type 1(MEN-1) : Clinical, biochemical and genetical investigations. showed good results below 100ng/ml. However, of those Acta Oncol 28 : 383-387, 1989 with prolactin levels > 100ng/ml, only 50% had a successful 6. Scheithauer BW, Laws ER Jr, Kovacs K, Horvath E, Randall RV, outcome. Therefore, the preoperative level of prolactin and Carney JA : Pituitary of the multiple endocrine neoplasia Type I syndrome. Semin Diagn Pathol 4 : 205-211, 1987 the tumor size influence the chance of successful surgical 7. Steven IS, Robert F : Disorders affecting multiple endocrine outcome. The overall postoperative normalization of prolactin systems, in Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, Mortin JB, Kasper DL(eds) : Harrison's principles of internal levels in prolactionoma was 60%. medicine. New York ; McGraw-Hill press 1998, pp2131-2138 In contrast, the combination of surgical treatment and 8. Timothy O, Diarmuid SO, Hossein G, Bernd WS, Michael JE, Jon AV H : Results of Treatment of Pituitary Disease in Multiple postoperative radiotherapy produced normal prolactin levels Endocrine Neoplasia, Type I. Neurosurgery 39 : 273-279, 1996

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