MULTIPLE ENDOCRINE NEOPLASIA TYPE 1

HORMONES AND DISORDERS OF MINERAL METABOLISM

0889-8529/00 $15.00

+

.OO

MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 Rajesh V. Thakker, MD, FRCP, FRCPath, FMedSci

Multiple endocrine neoplasiag6, 157 (MEN) is characterized by the occurrence of tumors involving two or more endocrine glands within a single patient. The disorder has been referred to previously as multiple endocrine adenopathy166or the pluriglandular ~yndrome.’~ Because glandular hyperplasia and malignancy also may occur in some patients, the term muZtiple endocrine neoplasia is now preferred.’&, 171 There are two major forms of MEN, referred to as type 1 and type 2. Each form is characterized by the development of tumors within specific endocrine glands (Table 1). The combined occurrence of tumors of the parathyroid glands, the pancreatic islet cells, and the anterior pituitary is characteristic of MEN type 1 (MEN-l), which is also referred to as Wermer’s syndrome.’” In addition to these tumors, adrenocortical, carcinoid, facial angiofibromas, collagenomas, and lipomatous tumors have been described in patients with MEN-1.96,165 In MEN type 2 (MEN-2), which is also called SippZe’s medullary thyroid carcinoma (MTC) occurs in association with pheochromocytoma. Three clinical variants referred to as MEN-2A, MEN-2B, and MTC-only are recognized.58, 13’ In MEN-2A, which is the most common variant, the development of MTC is associated with pheochromocytoma and parathyroid tumors. In MEN-2B, parathyroid involvement is rare, and the occurrence of MTC and pheochromocytoma is found in association with a marfanoid habitus, mucosal neuromas, medullated corneal fibers, and intestinal autonomic ganglion dysfunc-

From the Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, England

ENDOCRINOLOGYAND METABOLISM CLINICS OF NORTH AMERICA VOLUME 29 * NUMBER 3 * SEPTEMBER 2000

541

542

THAKKER

Table 1. MULTIPLE ENDOCRINE NEOPLASIA (MEN) SYNDROMES, THEIR CHARACTERISTIC TUMORS, AND ASSOCIATED GENETIC ABNORMALITIES Type (Chromosomal Location)

MEN-1 (llq13)

MEN-2 (10 cen-lOq.ll.2) MEN-2A MTC only MEN-28

Tumors

Gene and Most Frequently Mutated Codons (%)

Parathyroid Pancreatic islets Gastrinoma Insulinoma Glucagonoma VIPoma PPoma Pituitary (anterior) Prolactinoma Somatotrophinoma Corticotrophinoma Nonfunctioning Associated tumors Adrenocortical Carcinoid Lipoma Angiofibromas Collagenomas

MEN1: 83/84,4 bp del (-6%); 119, 3 bp del (-2%); 209-211,4 bp del (-4%); 514-516, del or ins (-7%)

Medullary thyroid carcinoma (MTC) Pheochromocytoma Parathyroid MTC

ref: 634, missense, e.g., Cys + Arg (-85%)

MTC Pheochromocytoma Associated abnormalities Mucosal neuromas Marfanoid habitus Medullated corneal nerve fibers Megacolon

ref: 618, missense (>50%) ref: 918, Met + Thr (>95%)

Del = deletion, ins = insertion; bp = base pairs. Autosomal dominant inheritance of the MEN syndromes has been established. Adapted from Thakker R V Multiple endocrine neoplasiasyndromes of the twentieth century. J Clin Endocrinol Metab 832617-2620, 1998; with permission.

tion leading to a megacolon. In the variant MTC-only, MTC seems to be the sole manifestation of the syndrome. Although MEN-1 and MEN-2 usually occur as distinct and separate syndromes, in some patients, tumors that are associated with MEN-1 and MEN-2 may develop. For example, patients sustaining islet cell tumors of the pancreas and pheochromocytomas,z, 147, or acromegaly and pheochromocytoma77,1"have been described. MEN in these patients 147 All of these forms of MEN may represent an "overlap" may be inherited as autosomal dominant syndromes104,152 or may occur sporadically, that is, without a family history.g6, 157 The distinction between sporadic and familial cases may sometimes be difficult because,

MULTIPLE ENDOCRINE NEOPLASIA TYPE 1

543

in some sporadic cases, the family history may be absent because the parent with the disease may have died before symptoms developed. This article discusses the main clinical features and molecular genetics of MEN-1, including recent progress in research. CLINICAL FEATURES OF MEN-1

The incidence of MEN-1 estimated from randomly chosen postmor88 The incidence ranges from 1%to 18% among tem studies is 0.25’%0.’~, patients with primary hyperparathyroidism20,31, 74 to 16% to 38% among patients with gastrinomas7,49 to less than 3% among patients with pituitary tumors.32,129,130 The disorder affects all age groups, with age ranging from 5 to 81 years. Clinical manifestations of the disorder develop in 80% of patients by the fifth decade.* The clinical manifestations of MEN-1 are related to the sites of tumors and to their products of secretion. In addition to the triad of parathyroid, pancreatic, and pituitary tumors (Fig. l), which constitute the major components of MEN-1, adrenocortical, carcinoid, facial angiofibromas, collagenomas, and lipomatous tumors have been described.35, 96, 154, 165 A patient may be considered to have MEN-1 if two of the three principal MEN-1-related tumors affecting the parathyroids, pancreatic islets, and anterior pituitary have occurred. Familial MEN-1 refers to a family in which there is one individual with at least two of the three principal MEN-1-related tumors plus one or more first-degree relatives with at least one of the three principal Parathyroid tumors are the first manifestation of MEN-1 in more than 85% of patients. In the remaining 15% of patients, the first manifestation may be an insulinoma or a prolactinoma.12,96, 156, 167 The combinations of these affected glands and their pathologic features, for example, hyperplasia or single or multiple adenomas of the parathyroid glands, have been reported to differ in members of the same family12,97, 156, 165, 167 and even between identical twins.5,53 MEN-1 is inherited as an autosomal dominant disorder in such families, but between 8% and 14% of patients with MEN-1 may have a nonfamilial (i.e., s p o r a d i ~ )form, ~~,~~~ and molecular genetic studies have confirmed the occurrence of de novo mutations of the MEN1 gene in approximately 10% of patient^.^ In the absence of treatment, these tumors have been associated with an earlier mortality.4”ln Parathyroid Tumors

Primary hyperparathyroidism is the most common feature of MEN1 and occurs in approximately 95% of patients.t Patients may present *References6, 12, 60, 96, 97, 133, 156, 165, and 167. tReferences 12, 47, 93, 96-98, 156, 165, and 167.

544

THAKKER

Parathyroid

Pancreas GAS 63.2% INS 27.3% GCG 2.1% NFT 1.1% unknown 6.3%

Associated Tumours Carcinoid 3.6% Adrenal cortical 5.0% Lipomata 0.9% Phaeochromocytoma0.5% Malignant Melanoma 0.5% Testicular Teratoma 0.5%

PRL 62.7% GH 22.4% ACTH 5.9% NFT 7.5% unknown 1.5%

Figure 1. The distribution of 384 MENl tumors in 220 MENl patients.165The proportions of patients in whom parathyroid, pancreatic, or pituitary tumors occurred are shown in the respective boxes, for example, 94.5% of patients had a parathyroid tumor. The Venn diagram indicatesthe proportions of patients with each combination of tumors, for example, 37.7% (25.9% + 11.8%) of patients had a parathyroid and a pancreatic tumor, whereas 2.3% of patients had a pancreatic tumor only. In addition to these tumors observed in one series,q65multiple facial angiofibromas have been observed in 88% of 32 patients, and collagenomas in 72% of patient^.^^ Parathyroid tumors represent the most common form of MENl tumors and occur in about 95% of patients, with pancreatic islet cell tumors occurring in about 40% of patients, and anterior pituitaly tumors occurring in about 30% of patients.'= The hormones secreted by each of these tumors are indicated: GAS = gastrin; INS= insulin; GCG = glucagon; NFT= nonfunctioningtumors; PRL= prolactin; GH =growth hormone; ACTH =adrenocorticotrophic hormone. (From Trump D, Farren B, Wooding C, et al: Clinical studies of multiple endocrine neoplasia type 1 [MEN11 Q J Med 89:653-669, 1996; with permission.)

with asymptomatic hypercalcemia, nephrolithiasis, osteitis fibrosa cystica, or vague symptoms associated with hypercalcemia (e.g., polyuria, polydipsia, constipation, or malaise), or occasionally with peptic ulcers. Biochemical investigations reveal hypercalcemia, usually in association with raised circulating parathyroid hormone concentrations. The hypercalcemia is usually mild, and severe hypercalcemia resulting in crisis or 133 Additional differences in the primary parathyroid cancer is hyperparathyroidism occurring in patients with MEN-1 versus other patients include an earlier age of onset (20 to 25 years versus 55 years) and an equal male-to-female ratio (1:l versus 1:3). Primary hyperparathyroidism in patients with MEN-1 is unusual before the age of 15 years. The age at which patients become affected has ranged from 20 to 21

MULTIPLE ENDOCRINE NEOPLASIA TYPE 1

545

years.'& Surgical removal of the abnormally overactive parathyroids in MEN-1 is the definitive treatment, but controversies remain regarding whether a subtotal or total parathyroidectomy should be performed at an early or late stage.75,121 Pancreatic Tumors The incidence of pancreatic islet cell tumors in patients with MEN1 ranges from 30% to 80% in different series." 63, 97, 165 Most of these tumors (Table 1)produce excessive amounts of hormone, such as gastrin, insulin, glucagon, or vasoactive intestinal polypeptide (VIP), and are associated with distinct clinical syndromes, although some tumors may remain nonfunctional or nonsecretory (Fig. 1).These pancreatic islet cell tumors have an earlier age of onset in patients with MEN-1 when compared with patients without MEN-1 Gastrinoma

Zollinger and Ellison178initially described two patients in whom non-beta islet cell tumors of the pancreas were associated with recurrent peptic ulceration and marked gastric acid production. Gastrin was subsequently extracted from such tumors.65,66 The association of recurrent peptic ulceration, marked gastric acid production, and non-beta islet cell tumors of the pancreas is referred to as Zollinger-Ellison syndrome. of Gastrin-secreting tumors (gastrinomas) represent over 50%12,47, 97, all pancreatic islet cell tumors in MEN-1 (Fig. l),and approximately 20% of patients with gastrinomas have MEN-1.lo5 Gastrinomas, which may also occur in the duodenal m u ~ o s a , 'are ~ ~the major cause of morbidity and mortality in MEN-1, and the prognosis is worse in patients with pancreatic primary metastases, ectopic Cushing's syndrome, or markedly elevated plasma gastrin concentration^.'^^ The majority of MEN-1 gastrinomas are malignant and will have metastasized in patients before a diagnosis is establi~hed.~~, 164 Gastrinomas in MEN-1 occur more often in patients aged more than 40 years,'& and recurrent severe multiple peptic ulcers, which may perforate, and cachexia are major contributors to the high mortality." In, 176 Patients with Zollinger-Ellison syndrome may also sustain diarrhea and steatorrhea. The diagnosis is established by demonstrating a raised fasting serum gastrin concentration in association with an increased basal gastric acid ~ecreti0n.I~~ Zollinger-Ellison syndrome in MEN-1 does not seem to occur in the absence of primary hyperparathyroidism,12,I4 and hypergastrinemia also has been reported to be associated with hypercalcemia'6'; thus, the diagnosis of ZollingerEllison syndrome may be difficult to make in some patients with MEN-1. Medical treatment of MEN1 patients with Zollinger-Ellison syndrome is directed toward reducing basal acid output to less than 10 mmol/L. This goal may be achieved by the parietal cell H', K+-ATPase inhibitor omeprazole, which has proved efficacious and has become the

546

THAKKER

drug of choice for gastrinomas.", Io3 Some patients may also require additional treatment with the histamine H,-receptor antagonists cimetidine or ranitidine.40.75, 76 The role of surgery in the treatment of gastrinomas in MEN-1 is controversial.25,75, s9, lo8, 137, 160 The ideal treatment for a nonmetastatic l6O Duodenal gastrinoma situated in the pancreas is surgical excision.137, gastrinomas, which occur more frequently in patients with MEN-1, also have been treated successfully by surgery..'14Nevertheless, in the majority of patients with MEN-1, gastrinomas are frequently multiple or extrapancreatic, and, with the exception of duodenal gastrinomas, surgery 63, lo8,lU, frequently has not been The results of a recent studylos revealed that only 16% of patients with MEN-1 were free of disease immediately after surgery. At 5 years, the rate had decreased to 6%. The respective outcomes in patients without MEN-1 were better at 45% and 40%. The treatment of disseminated gastrinomas is difficult. Chemotherapy with streptozocin and 5-fluorouracil, hormonal therapy with octreotide, which is a human somatostatin analogue, hepatic artery embolization, administration of human leukocyte interferon, and removal of all resectable tumor have sometimes been successful. lnsulinoma Beta islet cell tumors that secrete insulin represent 10% to 30% of all pancreatic 'tumors (Fig. 1) in patients with MEN-1." Insulinomas occur in association with gastrinomas in 112,165, 167 of patients, and the two tumors may arise at different times. Insulinomas occur more often in patients with MEN-1 who are less than 40 years of age, with many of these tumors arising in individuals before the age of 20 years,'& whereas in non-MEN-1 patients, insulinomas generally occur after the age of 40 years.96,165 Insulinomas may be the first manifestation of MEN1 in 10% of patients, and approximately 4% of patients presenting with insulinomas will have MEN-1.Iffi Patients with an insulinoma present with hypoglycemic symptoms that develop after a fast or exertion, with the symptoms improving after glucose intake. The most reliable test is a supervised 72-hour fast. Biochemical investigations reveal raised plasma insulin concentrations in association with hypoglycemia.46 Circulating concentrations of Cpeptide and proinsulin, which are also raised, may be useful in establishing the diagnosis. Medical treatment, which consists of frequent carbohydrate feeds and diazoxide or octreotide, is not always successful, and surgery is the optimal treatment. Most insulinomas are multiple and small. Preoperative localization with endoscopic ultrasonography, CT scanning, and celiac axis angiography, and preoperative and perioperative percutaneous transhepatic portal venous sampling and intraoperative direct pan*References 13, 63, 96, 144, 165167, 171, and 172.

MULTIPLE ENDOCRINE NEOPLASM TYPE 1

547

creatic ultrasonography have been undertaken to improve the success rate of ~urgery.3~~ 43, 4, 63, 64 Surgical treatment, which ranges from enucleation of a single tumor to a distal pancreatectomy or partial pancreatectomy, has been curative in many patients.39,63, 160 Chemotherapy, which consists of streptozocin and octreotide, and hepatic artery embolization have been used for metastatic disease. Glucagonoma

Alpha islet cell, glucagon-secreting, pancreatic tumors occur in less than 3% of patients with MEN-1 (Fig. 1).lo,34,86, 162, 165 The characteristic clinical manifestations of a skin rash (necrolytic migratory erythema), weight loss, anemia, and stomatitis may be absent, and the presence of the tumor may be detected in an asymptomatic patient with MEN-1 undergoing pancreatic imaging or by glucose intoleranck and hyperglucagonemia.lOT165 The tail of the pancreas is the most frequent site for glucagonomas, and surgical removal is the treatment of choice. Treatment may be difficult because approximately 50% to 80% of patients have metastases at the time of diagnosis.lO, Medical treatment with octreotide, streptozocin, or dimethyl triazeno imidazole carboxamide has been successful in some ~atients.9~ VlPoma

In patients with VIPomas, which are vasoactive intestinal peptide (VIP)-secreting pancreatic tumors, watery diarrhea, hypokalemia, and achlorhydria develop. This clinical syndrome has been referred to as the Verner-Morrison syndrome,168the WDHA syndrome,95or the VIPoma ~yndrome.'~ VIPomas have been reported in few patients with MEN-1.l" 24, The diagnosis is established by excluding laxative and diuretic abuse, by confirming a stool volume in excess of 0.5 to 1 L/day during a fast, and by documenting a markedly raised plasma VIP concentration. Surgical management of VIPomas, which are most commonly located in the tail of the pancreas, has been curative. In patients with unresectable tumor, treatment with octreotide or streptozocin has proved beneficial. PPoma

Tumors that secrete pancreatic polypeptide are found in a large number of patients with MEN-l.=, 60, 141No pathologic sequelae of excessive pancreatic polypeptide secretion are apparent, and the clinical significance of this substance is unknown, although the use of serum pancreatic polypeptide measurements has been suggested for the detection of pancreatic tumors in MEN-1.82,141 Many PPomas may have been unrecognized or classified as nonfunctioning tumors145(Fig. 1).

548

THAKKER

Somatostatinoma

Somatostatin, which inhibits growth hormone secretion, has been demonstrated to be present in the gastrointestinal tract, particularly in the pancreatic islets.l6,67, Pancreatic tumors secreting somatostatin are associated with the somatostatinoma syndrome, which is characterized by diabetes mellitus, gallstones, low acid output, steatorrhea, and weight loss.s1 Although some pancreatic islet cell tumors in MEN-1 secrete somatostatin, the somatostatinoma syndrome does not seem to have been reported in a patient with MEN-1, possibly reflecting the inhibitory action of somatostatin on endocrine cell proliferation and secretion. GHRHoma

Tumors that secrete growth hormone-releasing hormone (GHRH) have been reported in some patients with MEN-1," and it is estimated that approximately 33% of patients with GHRHomas have other MEN1-related tumors. GHRHomas may be diagnosed by finding elevated serum concentrations of growth hormone and GHRH. More than 50% of GHRHomas occur in the lung; 30% occur in the pancreas; and 10% lZ7 are found in the small intestine.lZ6,

Pituitary Tumors

The incidence of pituitary tumors in patients with MEN-1 ranges from 15% to 90% in different series.6,97, 165 Approximately 60% of MEN1-associated pituitary tumors secrete prolactin (Fig. 1); less than 25% secrete growth hormone; and 5% secrete adrenocorticotropic hormone. The remainder seem to be nonfunctioning, with some secreting glycoprotein subunits.+ Prolactinomas may be the first manifestation of MEN-1 in approximately 10% of patients, and somatotrophinomas occur more often in patients aged more than 40 years.165Less than 3% of patients with anterior pituitary tumors will have MEN-1.3z* IZ9, 130 The clinical manifestations of these tumors in patients with and without MEN-1 are similar and depend on the hormone secreted and the size of the pituitary tumor. Patients may present with the symptoms of hyperprolactinemia, such as amenorrhea, infertility, and galactorrhea in women and impotence in men, or with acromegaly or Cushing's disease. In addition, enlarging pituitary tumors may compress adjacent structures such as the optic chiasm or normal pituitary tissue and cause bitemporal hemianopia or hypopituitarism, respectively. Treatment of pituitary tumors in patients with and without MEN-1 is similar and consists of medical therapy or selective hypophysectomy by the transsphenoidal approach if feasible, with radiotherapy reserved for residual unresectable tumor. *References 15,47,48, 59, 70, 100, 105, 119, 130, and 165.

MULTIPLE ENDOCRINE NEOPLASM TYPE 1

549

Associated Tumors

Patients with MEN-1 may have tumors involving tissues other than the parathyroids, pancreas, and pituitary. Facial angiofibromas, collagenomas, thyroid, carcinoid, adrenocortical, and lipomatous tumors (Fig. 154, 1)have been described in association with Carcinoid Tumors

Carcinoid tumors, which occur in more than 3% of patients with MEN-1 (Fig. l), may be inherited as an autosomal dominant trait in association with MEN-1.45* The carcinoid tumor may be located in the bronchi,174the gastrointestinal tract,26,52, lzz, the pancreas,87or the thymus.@, 151 Bronchial carcinoids in MEN-1 predominantly occur in women (male-to-female ratio, 1:4), whereas thymic carcinoids predominantly occur in men, with cigarette smokers having a higher risk for developing tumors.15o,151 Most patients are asymptomatic and do not sustain the flushing attacks and dyspnea associated with the carcinoid syndrome, which usually develops after the tumor has become malignant and metastasized to the 1i~er.l~ l5O3

Adrenocortical Tumors

The incidence of asymptomatic adrenocortical tumors in MEN-1 has been reported to be as high as 40%.', 23, 13*, 139 Most of these tumors, which may include cortical adenomas, hyperplasia, multiple adenomas, nodular hyperplasia, or carcinomas, are nonfunctioningZ3, 139, 165; however, functioning adrenocortical tumors in patients with MEN-l have been documented to cause hypercortisolemia and Cushing's syndr0me,2~, 139, 165 and primary hyperaldosteronism, as in Conn's syndrome.l'f41,51, Lipomas

Subcutaneous lipomas occur in more than 33% of patients with MEN-1" 35, and frequently are multiple. In addition, visceral pleural or retroperitoneal lipomas may occur in patients with MEN-1. Facial Angiofibromas and Collagenomas

A study of 32 patients with MEN-1 revealed the occurrence of multiple facial angiofibromas in 88% of patients and collagenomas in 72% of ~atients.3~ MEN-1 angiofibromas were clinically and histologically identical to the tumors observed in patients with tuberous sclerosis, with the exception that, in MEN-1 patients, the angiofibromas were also present on the upper lip and vermilion border of the lip, areas that are not involved in tuberous sclerosis. These cutaneous findings may provide a useful means for possible presymptomatic diagnosis35of MEN-1

il!i +&

8

............ *:;<. .......... ......... ............ ........... ....... ........... ........... ......... ....... ...........

4 ........... ............ ....... ........... ........ ........... ......... r........... m ......... ....... ............ .......... ........ .........

s

2

8

P

m 550

MULTIPLE ENDOCRINE NEOPLASIA TYPE 1

551

in the relatives of a patient; however, the combined occurrence of MEN1 and tuberous sclerosis has also been observed.” Thyroid Tumors

Thyroid tumors consisting of adenomas, colloid goiters, and carcinomas have been reported in more than 25% of patients with MEN-161; however, the prevalence of thyroid disorders in the general population is high, and it has been suggested that the association of thyroid abnormalities in patients with MEN-1 may be incidental and not significant. MOLECULAR GENETICS Identification of the MEN7 Gene and Mutations

The gene causing MEN-1 was localized to chromosome llq13 by genetic mapping studies that investigated MEN-1-associated tumors for loss of heterozygosity (LOH) and by segregation studies in MEN-1 families.” 54, ss, 155, 156 The results of these studies, which were consistent with Knudson’s 8o for tumor development, indicated that the gene for MEN-1 represented a putative tumor suppressor gene.%,85, 156 Further genetic mapping studies defined a less than 300-kb region as the minimal critical segment that contained the gene. Characterization of genes from this region led to the identification in 1997 of the MEN2 gene,29,37, 158,159 which consists of 10 exons with a 1830-base pair (bp) coding region (see Fig. 1) that encodes a novel 610-amino acid protein referred to as MENIN.29 Mutations of the MEN2 gene (Figs. 2 and 3) have been identified.

Figure 2. The genomic organization of the MEN7 gene illustratinggermline (A) and somatic (B)mutations. The human MEN7 gene consists of 10 exons that span more than 9 kb of genomic DNA and encodes a 610-amino acid pr~tein.‘~The 1.83-kb coding region is organized into 9 exons (exons 2-10) and 8 introns (line, not to scale). The sizes of the exons (bars) range from 88 bp to 1312 bp and the sizes of the introns range from 41 bp to 1564 bp. The start (ATG) and stop (TGA) sites in exons 2 and 10, respectively, are indicated. Exon 1, the 5‘ part of exon 2 and 3’ part of exon 10 are untranslated (hatched bars). The locations of the two nuclear localization sites (NLS), which are at codons 479 to 497, and 588 to 608 at the C-terminus (thick horizontal lines), and the locations of the 3 domains, which are formed by codons 1 to 40 (exon 2), 139 to 242 (exons 2, 3, and 4), and 323 to 428 (exons 7, 8, and 9), and which interact with JunD (shaded bars), are shown. The sites of the 262 germline mutations (A) and 67 somatic mutations (B)are indicated by the vertical lines; the mis-sense (ms) and in-frame (in-fr) mutations are represented above the gene, and the nonsense (ns), frameshift (fs), and splice site (ss) mutations are represented below the gene. Mutations that have occurred more than 4 times (vertical scale) are indicated, and a total of 329 MEN7 mutations are represented. (From Pannett AA, Thakker RV: Multiple endocrine neoplasia type 1. Endocr Relat Cancer 6:449473, 1999; with permission.)

552

THAKKER

1 base pair deletion (codon 214) A Codon Number

213 214 215 216

Aminozid (WT) (m)

Ala

Wild Type (WT)

$ GT GTG GCT GCC G Y TG TGG CTG

Mutant (m)

Gly Val

Ala

Val Trp Leu

B Family 8/89

I I1 111

V

Q

k

A

43 40 39 36 34 28

35 32 30 27

C

-*

WT m

Mspl

I

117bp 19Obp

nbP

<-

Figure 3. See legend on opposite page

The total number of germline mutations of the MEN1 gene found in 21 studies* during the past 2 years in patients with MEN-1 is 262 (see Fig. 2). Approximately 22% are nonsense mutations, approximately 48% are frameshift deletions or insertions, 8% are in frame deletions or insertions, 5% are donor-splice site mutations, and approximately 17% are missense mutations.110More than 10% of the MEN1 mutations arise de novo and *References2, 8, 9, 19, 29, 30, 36, 56, 61, 62, 78,' 101, 102, 110, 115, 125, 128, 135, 146, 148, 149, 163, and 179.

h4LJLTIPLEENDOCRINE NEOPLASIA TYPE 1

553

may be transmitted to subsequent generations.” 9, 149 Five percent to 10% of patients with MEN-1 may not harbor mutations in the coding region of the MEN1 gene.’ 9, 29, 149, 15* These individuals may have mutations in the promoter or untranslated regions, which remain to be investigated. Most (75%) of the MEN1 mutations are inactivating1l0consistent with the mutations expected in a tumor suppressor gene. The mutations are not only diverse in their types but scattered (see Fig. 2) throughout the 1830-bp coding region of the MENl gene, with no evidence for clustering as observed in MEN-2 (Table 1).%Some of the mutations have been observed to occur several times in unrelated families (see Fig. 2), and four deletional and insertional mutations involving codons 83 and 84 (nt359 del4), 119 (K119 del), 209 to 211 (nt 738 del4), and 514 to 516 (nt 1656-7 del or ins C) account for approximately 19%of all the germline MEN1 mutations. These areas may represent potential ”hot spots” (Table 1). Such deletional and insertional hot spots may be associated with DNA sequence repeats that may consist of long tracts of either single nucleotides or shorter elements ranging from dinucleotides to octanucle~tides.~ Indeed, the DNA sequence in the vicinity of codons 83 and 84 in exon 2 (see Fig. 2) and codons 209 to 211 in exon 3 contains CT and CA dinucleotide repeats, respectively, flanking the 4-bp deletions. These mutations are consistent with a replication-slippage model in which there is misalignment of the dinucleotide repeat during replication, followed by excision of the 4-bp, single-stranded loop? h similar replication-slippage model may be involved at codons 119 to 120, which

Figure 3. Detection of mutation in exon 3 in family 8/89 by restriction enzyme analysis. DNA sequence analysis of individual 11.1 revealed a 1-bp deletion at the second position (GGT) of codon 214 (A). The deletion has caused a frameshift that continues to codon 223 before a stop codon (TGA) is encountered in the new frame. The 1-bp deletion results in the loss of an Mspl restriction enzyme site (C/CGG) from the normal (wild type, [wrl) sequence (A) and this has facilitated the detection of this mutation in the other affected members (11.4, 111.3, and 111.4) of this family (13). The mutant (m) PCR product is 190 bp, whereas the wild type (W)products are 117 bp and 73 bp (C). The affected individuals were heterozygous, and the unaffected members were homozygous for the wild type sequence. Individuals 111.6 and 111.10, who are 40 and 28 years old, respectively, are mutant gene carriers who are clinically and biochemically normal, and this is because of the agerelated penetrance of this dis~rder.~ These individuals would still require screening (see Fig. 4) by clinical, biochemical, and radiologic assessments, as they still have residual risks (i.e., 100% - age related penetrance) of 2%’ and more than 13%, respectively, of developing tumors by the age of 60 years.@Individuals are represented as: male (square);female (circle); unaffected (open); affected with parathyroid tumors (solid upper right quadrant of symbol), with gastrinoma (solid lower right quadrant of symbol), with prolactinoma (solid upper left quadrant of symbol); and unaffected mutant gene carriers (doffed open symbol). Individual 1.2 who is deceased but was known to be affected (tumor details not known) is shown as a solid symbol. The age is indicated below for each individual at diagnosis or at the time of the last biochemical screening. The standard size marker (S) in the form of the 1-kb ladder is indicated. Cosegregation of this mutation with MENl in family 8/89 and its absence in 110 alleles from 55 unrelated normal individuals (N,J indicates that it is not a common DNA sequence polymotphism. (Adapted from Bassett JHD, Forbes SA, Pannett AAJ, et a/: Characterisation of mutations in patients with multiple endocrine neoplasia type 1. Am J Hum Genet 62:232-244, 1998; with permission.)

554

THAKKER

Table 2. MEN-1-ASSOCIATED TUMORS IN FIVE UNRELATED FAMILIES WITH A 4-bp DELETION AT CODONS 209 AND 211 Family

Tumors

1

2

3

4

5

Parathyroid Gastrinoma Insulinoma Glucagonoma Prolactinoma Carcinoid

+ + -

++ +-

+ +-

+ + -

-

-

+ + + +

+

-

+

+-

+ -

-

presence; - = absence of tumors; bp = base pairs. RV: Multiple endocrine neoplasia--syndromes of the twentieth century. J Clin Endocrinol Metab 83:2617-2620, 1998; with permission. =

Adapted from Thakker

consist of AAG nucleotides encoding a lysine (K) residue. The deletions and insertions of codon 516 involve a poly(C), tract, and a slippedstrand mispairing model is the most likely mechanism associated with this mutational hot spot? The MENl gene seems to contain DNA sequences that render it susceptible to deletional and insertional mutations. Correlations between the MENl mutations and the clinical manifestations of the .disorder seem to be absent. A detailed study of five unrelated families with the same 4-bp deletion in codons 209 and 211 (Table 2) revealed a wide range of MEN-1-associated tumors?, 152 All of the affected family members had parathyroid tumors, but members of families 1, 3, 4, and 5 had gastrinomas, whereas members of family 2 had insulinomas. In addition, prolactinomas occurred in members of families 2,3,4, and 5 but not family 1, which was affected with carcinoid tumors. The apparent lack of genotype-phenotype correlations, which contrasts with the situation in MEN-2 (see Table 1)158together with the wide diversity of mutations in the 1830-bp coding region of the MENl gene make mutational analysis for diagnostic purposes in MEN-1 timeconsuming and expensive.*52 MEN7 Mutations in Sporadic Non-MEN-1 Endocrine Tumors

Parathyroid, pancreatic islet cell, and anterior pituitary tumors can occur as part of MEN-1 or, more commonly as sporadic nonfamilial tumors. Tumors from patients with MEN-1 have been observed to harbor the germline mutation together with a somatic LOH involving chromosome 11q13=,54, sf154, as expected from Knudson’s modelm,8o and the proposed role of the MENl gene as a tumor suppressor; however, LOH involving chromosome llq13, which is the location of MEN1, has also been observed in 5% to 50% of sporadic endocrine tumors, implicating

MULTIPLE ENDOCRINE NEOPLASM TYPE 1

555

the MEN1 gene in the etiology of these tumors.22,155 Somatic MEN1 mutations (see Fig. 2) have been detected in 13% of sporadic parathyroid 39% of gastrinomas (n = 54),92,170,180 17% of tumors (n = 150)127,50,69,132 insulinomas (n = 18),132,180 66% of VIPomas (n = 3),132, 13% of nonfunctioning pancreatic tumors (n = 15),71100% of glucagonomas (n = 2),'l 1.5% of adrenocortical tumors (n = 68)1" 36% of bronchial carcinoid tumors (n = 11)1364% of anterior pituitary adenomas (n = 117),117,146,179 10.5% of angiofibromas (n = 19),18and 17% of lipomas (n = These 67 somatic mutations are scattered throughout the 1830bp coding region (see Fig. 2); and 9% are nonsense mutations, 45% are frameshift deletions or insertions, 6% are in frame deletions or insertions, 4% are donor-splice site mutations, and 36% are missense mutations.110 A comparison of the locations of the somatic and germline mutations revealed a higher frequency (43% somatic versus 27% germline, P
The role of the MEN1 gene causing other inherited endocrine disorders in which either parathyroid or pituitary tumors occur as an isolated endocrinopathy has been investigated by mutational analysis. MEN1 mutations in five families with isolated hyperparathyroidism have been reported.56,115, 128, 135, 148 These mutations consisted of one nonsense (Tyr353Stop), one deletion (Leu414del 3bp), and three missense (Val184 Glu, Glu255Lys, and Leu267Pro) mutations. The sole occurrence of parathyroid tumors in these families harboring MEN1 mutations similar to those found in MEN-1 families is remarkable, and the mechanisms that determine the altered phenotypic expressions of these mutations remain to be elucidated. Mutational analysis studies in another inherited isolated endocrine tumor syndrome-familial isolated acromegaly-have not detected abnormalities of the MEN1 genet6', 149 even though segregation analysis in one family indicated that the gene was most likely located on chromosome llq13.5' Nonsense mutations (Tyr312Stop and Arg460Stop) have been detected" lO9 in MEN-1 families with the Burin or prolactinoma variantzm in which there is a high occurrence of prolactinomas and a low occurrence of gastrinomas.lW *References18, 27, 36, 56, 62, 69, 71, 92, 117, 163, 169, 170, 179, and 180.

556

THAKKER

Function of MEN-1 Protein

Initial analysis of the predicted amino acid sequence encoded by the MENl gene did not reveal homologies to any other proteins, sequence motifs, signal peptides, or consensus nuclear localization signalz9; thus, the putative function of the MEN-1 protein (MENIN) could not be deduced. Subsequently, studies based on immunofluorescence, Western blotting of subcellular fractions, and epitope tagging with enhanced green fluorescent protein revealed that MENIN was located primarily in the nucleus.68Furthermore, enhanced green fluorescent protein-tagged MENIN deletional constructs identified at least two independent nuclear localization signals that were located in the C-terminal quarter of the protein (see Fig. 2).68Interestingly, only one of the 94 MENl missense mutations and inframe deletions* results in an alteration of either of these putative nuclear localization signals (see Fig. 2). This missense mutation (Lys502Met), which involves an evolutionary conserved residue, was detected in a nonfunctioning sporadic pituitary All of the truncated MEN-1 proteins that would result from the 219 nonsense and frameshift mutations, if expressed, would lack at least one of these nuclear localization signals (see Fig. 2). The nuclear localization of MENIN suggested that it might act in the regulation of transcription, DNA replication, or the cell cycle. In an attempt to investigate this further and to identify proteins that may interact with MENIN, the yeast-two hybrid system was used. This system revealed that MENIN directly interacts with the N-terminus of the AP-1 transcriptional factor JunD to repress JunD-activated transcription.' Analysis of several MENl missense and deletional mutations indicated that the N-terminus and central domains of MENIN (see Fig. 2) have a critical role in MENIN-JunD interaction. Because JunD inhibits cell growth,7z,113, lZ4 an action that differs from that of other AP-1 proteins, the repressive effect of MENIN on JunD-mediated transcriptional activation would predict enhanced growth rather than the observed suppression in growth. This paradox may be explained by the involvement of other target genes and proteins influencing cell proliferation that may have interactions with the MENIN-JunD complex.' Such involvement is supported by the observation that disease-associated mutations that occur outside the domains interacting with JunD (see Fig. 2) are associated with normal MENIN-JunD binding, suggesting that MENIN may interact with other proteins that may influence JunD-mediated transcription. Further investigations are needed to elucidate the role of MENINJunD interactions in the control of endocrine cell proliferation. SCREENING IN MEN-1

In most patients, MEN-1 is inherited as an autosomal dominant disorder.lfi Occasionally, MEN-1 may arise sporadically (i.e., without a ~

*References 2, 8, 9, 19, 30, 36, 56, 61, 62, 78, 101, 102, 110, 115, 125, 128, 135, 146, 148, 149, 163, and 179.

MULTIPLE ENDOCRINE NEOPLASIA TYPE 1

557

family history), although it may be difficult to make the distinction between sporadic and familial forms.'54*157 In some cases, the family history may be absent because the parent with MEN-1 is not available or may have died before any manifestations of MEN-1 developed. Other cases may be caused by de novo mutations, which are transmitted in an autosomal dominant manner in future generations.&9, 149 Although MEN1 is an uncommon disorder, because of its autosomal dominant inheritance, the finding of MEN-1 in a patient has important implications for other family members. First-degree relatives have approximately a 50% risk for the d i ~ e a s e . 9 ~Screening f'~~ for MEN-1 involves the detection of tumors and ascertainment of the germline genetic state, that is, normal or mutant gene carrier. The detection of tumors entails clinical, biochemical, and radiologic investigations for MEN-1-associated tumors.lffiThe recent cloning of the MENl genez9,158 has facilitated the identification of individuals who have mutations and hence are at high risk for the disease (see Figs. 2 and 3). Genetic Analysis

Molecular genetic analysis for MEN-1, either by detecting mutations (see Fig. 3) or by performing segregation studies using linked markers, could be performed to identify individuals who are mutant carriers and at high risk for tumors.=, 154 The advantages of DNA analysis are that it requires a single blood sample and does not, in theory, need to be repeated. The analysis is independent of the age of the individual and provides an objective result. Such mutational analysis could be undertaken in children around the first decade (tumors have developed by the age of 5 years6)and appropriate intervention in the form of biochemical testing or treatment could be Unfortunately, the great diversity of MENl mutations,110the widely scattered locations of the mutations (see Fig. 2), and the lack of genotype-phenotype correlation (see Table 2) would make such mutational screening time-consuming, arduous, and and, as a result, screening is not widely available. An integrated program of mutational analysis to identify mutant gene carriers and biochemical screening to detect the development of tumors would be an advantage.= A DNA test identifying an individual as a mutant gene carrier would lead not to immediate medical or surgical treatment but to earlier and more frequent biochemical and radiologic screening, whereas a DNA result indicating that an individual is not at risk would lead to a decision for no further clinical investigations (Fig. 4).In the future, the identification of MENl mutations may be of help in the clinical management of patients and their families. Detection of MEN-1 Tumors

Biochemical screening for the development of MEN-1 tumors in asymptomatic members (see Figs. 3 and 4)of families with MEN-1 is of

558

THAKKER

Asymptomatic relative of MEN1 patient in whom germ-line mutation identified

Test for MEN1 mutations by RE, ASO, SSCP analysis I

Mutant carrier

I

'

i

Age e4Qyears

Serum Ca++, PRL and assessment for insulinoma

result

Nonmutant carrier

W l L

1 I

I invZgLns not necessary

I

Serum Ca++, PRL and assessment for gastrinoma and acromegaly

result

Re-screen at 6-12 months

Proceed to further appropriate investigations

Proceed to further appropriate investigations and treatment

Figure 4. An approach to screening in an asymptomatic relative of a patient with MENI. The relative should first have undergone a clinical evaluation for MENI-associated tumors to establish that the individual is asymptomatic. Relatives who are symptomatic, who could also be tested for MEN7 mutations, should proceed to appropriate investigations and management. Mutational analysis for MEN1 is not routinely available at present, and this protocol could instead be adapted for first-degree re1ati~es.l~~ The MEN7 mutation may be identified directly by DNA sequence analysis, or by restriction enzyme (RE) (see Fig. 3), allele-specific oligonucleotide (ASO) hybridizati~n,~, 155 or another method such as singlestranded conformational polymorphism (SSCP) analysi~.~ The use of mutational analysis and such screening methods in children is controversial and varies in different countries. It has been suggested that nonessential genetic testing in a child, who is not old enough to make important long-term decisions, should be deferred.3 However, the finding that a child from a family with MEN1 does not have any MEN7 mutations removes the burden of repeated clinical, biochemical, and radiologic investigations and enables health resources to be more effectively directed towards those children who are MEN7 mutant gene carriers.

MULTIPLE ENDOCRINE NEOPLASIA TYPE 1

559

great importance because early diagnosis and treatment of these tumors may help to reduce morbidity and mortality.u, 173 The age-related penetrance (i.e., the proportion of gene carriers manifesting symptoms or signs of the disease by a given age) has been ascertained? The mutation seems to be nonpenetrant below the age of 5 years. Thereafter, the mutant MEN1 gene has a penetrance greater than 50% by 20 years of age and greater than 95% by 40 years.9 Screening for MEN-1 tumors is difficult because the clinical and biochemical manifestations in members of any one family are not uniformly similar (see Fig. 3).* Attempts to screen for the development of MEN-1 tumors in the asymptomatic relatives of an affected individual have depended largely on measuring the serum concentrations of calcium, gastrointestinal hormones (e.g., gastrin) and prolactin, and on ultrasound and radiologic imaging of the abdomen and pituitary.I2Z 97, 167 Parathyroid overactivity causing hypercalcemia is almost invariably the first manifestation of the disorder and has become a useful and easy biochemical screening investigation.1z,97,165, 167 In addition, hyperprolactinemia, which may be asymptomatic, may represent the first manifestation in approximately 10% of patients and may also be a useful and easy biochemical screening investigation.Pancreatic involvement in asymptomatic individuals has been detected by estimating the fasting plasma concentrations of gastrin, pancreatic polypeptide, and glucagon, and by abdominal imaging'", 165; however, in one study, a stimulatory meal test was a better method for detecting pancreatic disease in individuals who had no demonstrable pancreatic tumors by CT.I4"An exaggerated increase in serum gastrin or pancreatic polypeptide or both proved to be a reliable early indicator for the development of pancreatic tumors in these individuals. Individuals at high risk for MEN-1 (i.e., mutant gene carriers) should undergo biochemical screening (Fig. 4) at least once per m u m . In addition, baseline pituitary and abdominal imaging should be performed and repeated at 5- to 10-year intervals. Screening should commence in early childhood because the disease has developed in some individuals by the age of 5 years.6,88 Screening should continue for life because in some individuals the disease does not develop until the eighth decade?", 167 The screening history and physical examination should be directed toward eliciting the symptoms and signs of hypercalcemia, nephrolithiasis, peptic ulcer disease, neuroglycopenia, hypopituitarism, galactorrhea and amenorrhea in women, acromegaly, Cushing's disease, visual field loss, and the presence of subcutaneous lipomata, angiofibromas, and collagenomas. Biochemical screening should include serum calcium and prolactin estimations in all individuals and measurement of gastrointestinal hormones such as gastrin. More specific endocrine function tests should be reserved for individuals who have symptoms or signs suggestive of a clinical syndrome. *References 1, 7, 20, 29, 31, 32, 49, 60, 74, 88, 97, 129, 130, 133, 156, 158, and 165.

560

THAKKER

SUMMARY

Combined clinical and laboratory investigations of MEN-1 have resulted in an increased understanding of this disorder, which may be inherited as an autosomal dominant condition. Defining the features of each disease manifestation in MEN-1 has improved patient management and treatment and has facilitated a screening protocol. Application of the techniques of molecular biology has enabled the identification of the gene causing MEN-1 and the detection of mutations in patients. The protein encoded by the MENl gene has been shown to be involved in the regulation of JunD-mediated transcription, but much still remains to be elucidated. Recent advances permit the identification of mutant MENl gene carriers who are at a high risk for this disorder and who require regular and biochemical screening to detect the development of endocrine tumors. ACKNOWLEDGMENTS The author thanks the Medical Research Council in the United Kingdom for its support, Paul T. Christie, PhD, Anna A.J. Pannett, PhD, and Brian Harding, PhD for help in the preparation of some of the figures; and Julie Allen for typing the manuscript and expert secretarial assistance.

References 1. Aganval SK, Guru SC, Heppner C, et al: Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Cell 84:730-735, 1999 2. Agarwal SK, Kester MB, Debelenko LV, et al: Germline mutations of the MENl gene in familial multiple endocrine neoplasia type 1 and related states. Hum Mol Genet 61169-1175, 1997 3. American Society of Human Genetics Board of Directors and the American College of Medical Genetics Boards of Directors: Points to consider: Ethical, legal and psychosocial implications of genetic testing in children and adolescents. Am J Hum Genet 57123S1241, 1995 4. Asa SL, Singer W, Kovacs K, et al: Pancreatic endocrine tumor producing growth hormone releasing hormone associated with multiple endocrine neoplasia type 1 syndrome. Acta Endocrinol 115331-335, 1987 5. Bahn FS, Scheithauner BW, Van Hearden JA, et al: Nonidentical expressions of multiple endocrine neoplasia, type 1, in identical twins. Mayo Clinic Proc 61:689696, 1986 6. Ballad HS, Frame 8, Hartstock C: Familial multiple endocrine adenoma-peptic ulcer complex. Medicine 43:481-515, 1964 7. Bardram L, Stage JG: Frequency of endocrine disorders in patients with ZollingerEllison syndrome: A collective surgical experience. Scand J Gastroenterol 20:211-145, 1985 8. Bartsch D, Kopp I, Bergenfelz A, et ak MENl gene mutations in 12 MENl families and their associated tumors. Eur J Endocrinol 139:41&420, 1998 9. Bassett JHD, Forbes SA, Pannett AAJ, et al: Characterisation of mutations in patients with multiple endocrine neoplasia type 1 (MENl). Am J Hum Genet 62232-244, 1998 10. Bassett JHD, Williamson C, Pang J, et al: Glucagonomas in multiple endocrine neoplasia type 1. J Endocrinol 152:68, 1997 11. Beckers A, Abs R, Willems PJ, et al: Aldosterone-secreting adrenal adenoma as a part

MULTIPLE ENDOCRINE NEOPLASIA TYPE 1

561

of multiple endocrine neoplasia type 1 (MENl): Loss of heterozygosity for polymorphic chromosome 11 deoxyribonucleotide acid markers, including the MENl locus. J Clin Endocrinol Metab 75:564-570, 1992 12. Benson L, Ljunghall S, Akerstrom G, et al: Hyperparathyroidism presenting as the first lesion in multiple endocrine neoplasia type 1. Am J Med 82731-737, 1987 13. Berdjis CC: Pluriglandular syndrome. II. Multiple endocrine adenomas in man: A report of five cases and a review of the literature. Oncologia 15:288-311, 1962 14. Betts JB, OMalley BP, Rosenthal FD: Hyperparathyroidism: A prerequisite for Zollinger-Ellison syndrome in multiple endocrine adenomatosis type 1. A report of a further family and a review of the literature. Q J Med 49:69-76, 1980 15. Bidart JM, Baudin E, Troalen F, et al: Eutopic and ectopic production of glycoprotein hormones alpha and beta subunits. Ann Endocrinol58125-128, 1997 16. Bloom SR, Polak JM, West AM: Somatostatin content of pancreatic endocrine tumors. Metabolism 271235-1238,1978 17. Bloom SR, Polak JM, Pearse AGE: Vasoactive intestinal peptide and watery diarrhea syndrome. Lancet 214-16, 1973 18. Boni R, Vortmeyer AO, Pack S, et al: Somatic mutations of the MENl tumor suppressor gene detected in sporadic angiofibromas. J Invest Dermatol111:539-540,1998 19. Bordi C, Falchetti A, Azzoni C, et al: Aggressive forms of gastric neuroendocrine tumors in multiple endocrine neoplasia type 1. Am J Surg Pathol 21:1075-1082, 1997 20. Brandi ML, M a n SJ, Aubach GD, et al: Familial multiple endocrine neoplasia type 1: A new look at pathophysiology. Endocr Rev 8:391412, 1987 21. Brown CH, Crile G Jr: Pancreatic adenoma with intractable diarrhea, hypokalemia and hypercalcemia. JAMA 190:30-34, 1964 22. Bystrom C, Larsson C, Blomberg C, et al: Localization of the MEN 1 gene to a small region within chromosome llq13 by deletion mapping in tumors. Proc Natl Acad Sci USA 871968-1972,1990 23. Burgess JR, Harle RA, Tucker P, et al: Adrenal lesions in a large kindred with multiple endocrine neoplasia type 1. Arch Surg 131:699-702,1996 24. Burkhardt A: Das Verner-Morrison Zyndrome. Klin Pathol Anat Klin Wochenschr 541-11, 1976 25. Cadiot G, Vuagnat A, Doukhan I, et al: Prognostic factors in patients with ZollingerEllison syndrome and multiple endocrine neoplasia type 1: Groupe d’etude des Neoplasies Endocriniennes Multiples (GENEM and groupe de Recherche et &Etude du Syndrome de Zollinger-Ellison (GRESZE). Gastroenterology 116:28&293, 1999 26. Cadiot G, Laurent-Puig P, Thuille B, et al: Is the multiple endocrine neoplasia type I gene a suppressor for fundic argyrophil tumors in the Zollinger-Ellison syndrome? Gastroenterology 105:579-582, 1993 27. Carling T, Correea P, Hessman 0, et al: Parathyroid MEN2 gene mutations in relation to clinical characteristics of nonfamilial primary hyperparathyroidism. J Clin Endocrino1 Metab 83:2951-2954, 1998 28. Carney JA, Go VLW, Gordin H, et al: Familial pheochromocytoma and islet cell tumor of the pancreas. Am J Med 68:515521, 1980 29. Chandrasekharappa SC, Guru SC, Manickam P, et al: Positional cloning of the gene for multiple endocrine neoplasia type 1. Science 276:404407, 1997 30. Chic0 A, Gallart L, Mato E, et al: A novel germline mutation in exon 5 of the multiple endocrine neoplasia type 1 gene. J Mol Med 769337439, 1998 31. Christensson T Familial hyperparathyroidism. Ann Intern Med 85:614415, 1976 32. Corbetta S, Pizzocaro A, Peracchi M, et ak Multiple endocrine neoplasia type 1 in patients with recognized pituitary tumors of different types. Clin Endocrinol 47507-512, 1997 33. Croisier JC, Lehy T, Zeitoun P: A2 cell pancreatic microadenomas in a case of multiple endocrine adenomatosis. Cancer 28707-713, 1971 34. Croughs RJM, Hulsmans HAM, Israel DE, et ak Glucagonoma as part of the polyglandular adenoma syndrome. Am J Med 52690498,1972 35. Darling TN, Skarulis MC, Steinberg SM, et ak Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1. Arch Dermatol 1332353-861, 1997

562

THAKKER

36. Debelenko LV, Brambilla E, Agarwal SK, et al: Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung. Hum Mol Genet 6:228!%2290, 1997 37. Debelenko LV, Emmert Buck MR, Manickam F', et al: Haplotype analysis defines a minimal interval for the multiple endocrine neoplasia type 1 (MENl) gene. Cancer Res 571039-1042, 1997 38. Delcore R, Hermreck AS, Friesen SR Selective surgical management of correctable hypergastrinemia. Surgery 106:1094-1102, 1989 39. Demeure MJ, Klonoff DC, Karam JH, et al: Insulinomas associated with multiple endocrine neoplasia type I: The need for a different surgical approach. Surgery 110998-1005, 1991 40. Deveney CW, Stein S, Way LW Cimetidine in the treatment of Zollinger-Ellison syndrome. Am J Surg 146116-123, 1983 41. Dluhy RG, Williams G H Primary aldosteronism in a hypertensive acromegalic patient. J Clin Endocrinol29:1319-1324, 1969 42. Doherty GM, Olson JA, Frisella MM, et al: Lethality of multiple endocrine neoplasia type 1. World J Surg 22:581-585,1998 43. Doherty GM, Doppman JL, Shawker TH, et al: Results of a prospective strategy to diagnose, localize and resect insulinomas. Surgery 110:989-996, 1991 44. Doppman JL, Miller DL, Chang R Insulinomas: Localisation with selective intraarterial injection of calcium. Radiology 178237-242, 1991 45. Duh QY, Hybarger CD,Geist R, et al: Carcinoids associated with multiple endocrine neoplasia syndromes. Am J Surg 154:142-148, 1987 46. Eastman RC, Kahn C R Hypoglycemia. In Moore WT, Eastman EC (eds): Diagnostic Endocrinology. Toronto, BC Decker, 1990, pp 183-191 47. Eberle F, Grun R Multiple endocrine neoplasia type I (MEN-I). Ergbeg IM Med Kinderheilkd 4676-149, 1981 48. Farid NR, Buchler S, Russell NA, et al: Prolactinomas in familial multiple endocrine neoplasia syndrome type I: Relationship to HLA and carcinoid tumors. Am J Med 69:874-880,%1980 49. Farley DR,' Van Heerden JA, Grant CS, et al: The Zollinger-Ellison syndrome: A collective surgical experience. AM Surg 215:561-567, 1992 50. Famebo F, The BT, Kytola S, et al: Alterations of the MEN2 gene in sporadic parathyroid tumors. J Clin Endocrinol Metab 83:2627-2630, 1998 51. Fertig A, Welsley M, Lynn J A Primary hyperparathyroidism in a patient with COM'S syndrome. Postgrad Med J 56:45-47, 1980 52. Fisher ER, Hicks J: Further pathologic observations on the syndrome of peptic ulcer and multiple endocrine tumors. Gastroenterology 38458-466, 1960 53. Flanagan D, Armitage M, Clein P, et al: Prolactinoma presenting in identical twins with multiple endocrine neoplasia type 1. Clin Endocrinol45:117-120, 1996 54. Friedman E, Sakaguchi K, Bale AE, et al: Clonality of parathyroid tumors in familial multiple endocrine neoplasia type 1. N Engl J Med 321:213-218, 1989 55. Friesen SR, Kimmel JR, Tomita T Pancreatic polypeptide as screening marker for pancreatic polypeptide apudomas in multiple endocrinopathies. Am J Surg 139:6172, 1980 56. Fuiimori M. Shirahama S. Sakurai A, et al: Novel V184E MENl germline mutation in a fapanese 'kindred with familial hyperparathyroidism. Am J MGd Genet 80:221-222, 1998 ~. .-

57. Gadelha MR, Une KN, Vaisman M, et al: Localization of the isolated familial somatotropinoma gene to a 7.4 Mb region at chromosome llq13 by allelotype and haplotype analysis [abstract]. In Program and Abstracts of the Endocrine Society's 81st Annual Meeting, 1999, San Diego 58. Gage1 RF, Cotes GJ: Ref protooncogene mutations in multiple endocrine neoplasia type 2. In Bilezikian JF', Raisz LG, Rodan GA (eds): Principles of Bone Biology. San Diego, Academic Press, 1996, pp 799-780 59. Gaitan D, Loosen PT, Orth D N Two patients with Cushing's disease in a kindred with multiple endocrine neoplasia type I. J Clin Endocrinol Metab 76:1580-1582,1993 60. Gelston AL, Delisle MB, Pate1 YC: Multiple endocrine adenomatosis type 1occurrence

MLnTIPLE ENDOCRINE NEOPLASIA TYPE 1

563

in an octogenarian with high levels of circulating pancreatic polypeptide. JAMA 24766%566,1982 61. Giraud S, Zhang CX, Serovasinilnikova 0, et al: Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. Am J Hum Genet 63:455467, 1998 62. Gortz 8, Roth J, Speel EJM, et al: MENl gene mutation analysis of sporadic adrenocortical lesions. Int J Cancer 80:37%379, 1999 63. Grama D, Skogseid B, Wilander E, et al: Pancreatic tumors in multiple endocrine neoplasia type 1: Clinical presentation and surgical treatment. World J Surg 16:611619, 1992 64. Grant CS, van Heerden JA, Charboneau JW, et al: Insulinoma: The value of intraoperative ultrasonography. Arch Surg 123:84%850, 1988 65. Gregory RA, Grossman MI, Tracy HJ, et a1 Nature of gastric secretagogue in Zollinger-Ellison tumors. Lancet 2543-544, 1967 66. Gregory RA, Tracy H, French JM, et al: Extraction of a gastrin-like substance from a pancreatic tumor in a case of Zollinger-Ellison syndrome. Lancet 1:1045-1048, 1960 67. Guillemin R Some thoughts on current research with somatostatin. Metabolism 27145S1461, 1978 68. Guru SC, Goldsmith PK, Burns AL, et al: Menin, the product of the MEN2 gene, is a nuclear protein. Proc Natl Acad Sci USA 95:1630-1634, 1998 69. Heppner C, Kester MB, Agarwal SK, et al: Somatic mutation of the MENl gene in parathyroid tumors. Nat Genet 16:375-378, 1997 70. Hershon KS, Kelly WA, Shaw CM, et al: Prolactinomas as part of the multiple endocrine neoplastic syndrome type 1. Am J Med 74:713-720, 1983 71. Hessman 0, Lindberg D, Skogseid B, et al: Mutation of the multiple endocrine neoplasia type 1 gene in nonfamilial, malignant tumors of the endocrine pancreas. Cancer Res 58:377-379, 1998 72. Hirai SI, Ryseck RP, Mechta F, et al: Characterization of JunD: A new member of the jun proto-oncogene family. EMBO J 8:1433-1439, 1989 73. Ilgren EB, Westmoreland D: Tuberous sclerosis: Unusual association in four cases. J Clin Pathol37272-278, 1984 74. Jackson CE, Boonstra CE: The relationship of hereditary hyperparathyroidism to endocrine adenomatosis. Am J Med 43:727-734, 1967 75. Jensen RT: Management of the Zollinger-Ellison syndrome in patients with multiple endocrine neoplasia type 1. J Intern Med 243:477488,1998 76. Jensen RT, Collen MJ, McArthur KE: Comparison of the effectiveness of ranitidine and cimetidine in inhibiting acid secretion in patients with gastric hypersecretory states. Am J Med 7790-105, 1984 77. Kahn MR, Mullen D A Pheochromocytoma without hypertension: Report of a case with acromegaly. JAMA 1887675,1964 78. Kishi M, Tsukada T, Shimizu S, et a1 A large germline deletion of the MENl gene in a family with multiple endocrine neoplasia type 1. Jpn J Cancer Res 891-5, 1998 79. Knudson AG, Strong LC, Anderson DE: Heredity and cancer in man. Prog Med Genet 9:113-158, 1973 80. Knudson AG: Mutation and cancer: Statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820-823, 1971 81. Krejs GJ, Orci L, Conlon JM, et al: Somatostatinoma syndrome. N Engl J Med 301:285-292, 1979 82. Lamers CBHW, Diemel CM. Basal and postatropine serum pancreatic polypeptide concentrations in familial multiple endocrine neoplasia type I. J Clin Endocrinol Metab 5774-778, 1982 83. Landis CA, Masters SB, Spada A, et al: GTPase inhibiting mutations activate the chain of Gs and stimulate adenyl cyclase in human pituitary tumors. Nature 340692696, 1989 84. Larsson C, Shepherd J, Nakamura Y, et ak Predictive testing for multiple endocrine neoplasia type 1 using DNA polymorphisms. J Clin Invest 89313441349, 1992 85. Larsson C, Skogseid B, Oberg K, et ak Multiple endocrine neoplasia type I gene maps to chromosome 11 and is lost in insulinoma. Nature 332:85-87, 1988

564

THAKKER

86. Leclerc J, Vican F, Laurent J, et al: Tumeur insulaire avec diarrhee et diabete (glucagonoma) associee a un hyperparathyroidism-resultat eloingne du traitement par 1. streptozotocine loco-regionale. Ann Endocrinol (Paris) 38:15>154, 1977 87. Lee CH, Ching KN, Lui WY, et al: Carcinoid tumor of the pancreas causing the diarrheogenic syndrome: Report of a case combined with multiple endocrine neoplasia type 1. Surgery 99:12%129, 1980 88. Lips CJM, Vasen HFA, Lamers CBHW Multiple endocrine neoplasia syndromes. CRC Crit Rev Oncol Hematol2:117-184, 1984 89. Lowney JK, Frisella MM, Larimore TC, et al: Pancreatic islet cell tumor metastasis in multiple endocrine neoplasia type 1: Correlation with primary tumor size. Surgery 124:1043-1048, 1998 90. Lundbeck K Somatostatin: Clinical importance and outlook. Metabolism 2714631469, 1978 91. Lyons J, Landis CA, Harsh G, et al: Two G protein oncogenes in human endocrine tumors. Science 249:655-659, 1990 92. Mailman MD, Muscarella P, Schrimer WJ, et al: Identification of MENl mutations in sporadic enteropancreatic neuroendocrine tumors by analysis of paraffin-embedded tissue. Clin Chem 4529-34, 1999 93. Majewski JT, Wilson SD: The MEA-I syndrome: An all or none phenomenon. Surgery 863474484, 1979 94. Mallette LE, Blevins T, Jordan PH, et al: Autogenous parathyroid grafts for generalised primary hyperplasia: Contrasting outcomes in sporadic versus multiple endocrine neoplasia type I. Surgery 101:738-745, 1987 95. Marks IN, Bank S, Louw JH: Islet cell tumor of the pancreas with reversible watery diarrhea and achlorhydria. Gastroenterology 52695708, 1967 96. Marx SJ: Multiple endocrine neoplasia type 1. In Vogelstein 8, Kinzler KW (eds): Genetic Basis of Human Cancer. New York, McGraw Hill, 1998, pp 489-506 97. Marx SJ, Vinik AI, Sauten RJ, et al: Multiple endocrine neoplasia type 1: Assessment of laboratory tests to screen for the gene in a large kindred. Medicine 65:22&241, 1986 98. Marx SJ, Spiegel AM, Levine MA, et al: Familial hypocalciuric hypercalcemia: The relation to primary parathyroid hyperplasia. N Engl J Med 307416426, 1982 99. Marynick SP, Fagadan WR, Duncan L A Malignant glucagonoma syndrome: Response to chemotherapy. Ann Intern Med 93:453-454, 1980 Jensen RT Cushing’s syndrome in patients with the Zollinger100. Maton PN, Gardner JD, Ellison syndrome. N Engl J Med 325:l-5, 1986 101. Mayr 8, Brabant G, vonzurMuhlen A: Menin mutations in MENl patients. J Clin Endocrinol Metab 83:3004-3005, 1998 102. Mayr B, Apenberg S, Rothamel T, et al: Menin mutations in patients with multiple endocrine neoplasia type 1. Eur J Endocrinol 137684-687, 1997 103. McArthur KE, Collen MJ, Maton PN: Omeprazole: Effective convenient therapy for Zollinger-Ellison syndrome. Gastroenterology 88:939-944, 1985 104. McKusick VA Mendelian Inheritance in Man. Baltimore, Johns Hopkins University Press, 1998 105. Metz DC, Jensen RT, Bale A, et al: Multiple endocrine neoplasia type 1: Clinical features and management. In Bilezekian JP, Levine MA, Marcus R (eds): The Parathyroids. New York, Raven Press, 1994, pp 591-636 106. Miller GL, Wynn J: Acromegaly, pheochromocytoma, toxic goitre, diabetes mellitus, and endometriosis. Arch Intern Med 127299-303, 1971 107. Moertel CG, Hanley JA, Johnson L A Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet cell carcinoma. N Engl J Med 303:1189-1194, 1980 108. Norton JA, Fraker DL, Alexander R, et al: Surgery to cure the Zollinger-Ellison syndrome. N Eng J Med 341:63-, 1999 109. Olufenii SE, Green JS, Manikam P, et al: Common ancestral mutation in the MENl gene is likely responsible for the prolactinoma variant of MENl (MENls-) in four kindreds from Newfoundland. Hum Mutat 11:26@269, 1998 110. Pannett AAJ, Thakker RV Multiple endocrine neoplasia type 1 (MEN1). EndocrineRelated Cancer 6449473, 1999

MULTIPLE ENDOCRINE NEOPLASM TYPE 1

565

111. Pannett AAJ, Thakker RV: Meta-analysis of 31 studies reporting 344 mutations in the multiple endocrine neoplasia type 1 (MEN1) gene. J Bone Miner Res 143-10,1999 112. Peurifoy JT, Gomez LG, Thompson JC: Separate pancreatic gastrin cell and beta-cell adenomas: Report of a patient with multiple endocrine adenomatosis type 1. Arch Surg 114956-958, 1979 113. Pfarr CM, Mechta F, Spyrou G, et al: Mouse JunD negatively regulates fibroblast growth and antagonizes transformation by ras. Cell 76:747-760, 1994 114. Pipeleers-Marichal M, Somers G, Willems G, et a1 Gastrinomas in the duodenums of patients with multiple endocrine neoplasia type 1 and the Zollinger-Ellison syndrome. N Engl J Med 322:72>727, 1990 115. Poncin J, Abs R, Velkeniers B, et al: Mutation analysis of the MENl gene in Belgian patients with multiple endocrine neoplasia type 1 and related diseases. Hum Mutat 13:54-60, 1999 116. Ponder 8: 1998. Clinical expressions of multiple endocrine neoplasia type 2. In Vogelstein B, Kinzler KW (eds): The Genetic Basis of Human Cancer. New York, McGraw-Hill, 1998, pp 486-487 117. Prezant TR. Levine 1. Melmed S Molecular characterization of the Men 1 tumor suppressor ‘gene in sporadic pituitary tumors. J Clin Endocrinol Metab 8333881391, 1998 118. Prim RA, Gamutos 01, Sellu D, et al: Subtotal parathyroidectomy for primary chief cell hyperplasia of multiple endocrine neoplasia type 1 syndrome. Ann Surg 193:2630,1981 119. Prosser PR, Karom JH, Townsend JJ, et al: Prolactin-secreting pituitary adenomas in multiple endocrine adenomatosis type 1. AM Intern Med 91:4144, 1979 Henneman PH, Graf WS: Co-existing primary hyperparathyroidism and 120. Raker JW, Cushing’s syndrome. J Clin Endocrinol Metab 22273-280, 1962 121. Rizzoli R, Green J, Marx SJ: Primary hyperparathyroidism in familial multiple endocrine neoplasia type 1:Long-term follow-up of serum calcium levels after parathyroidectomy. Am J Med 78:467-474,1985 122. Rode J, Dhillon M, Cotton PB, et al: Carcinoid tumor of stomach and primary hyperparathyroidism: A new association. J Clin Pathol40:546-551, 1987 123. Ruszniewski P, Podevin P, Cadiot G, et al: Clinical, anatomical, and evolutive features of patients with the Zollinger-Ellison syndrome combined with type I multiple endocrine neoplasia. Pancreas 8:295304, 1993 124. Ryder K, Lanahan A, Perez-Albuerne B, et al: junD: A third member of the jun gene family. Proc Natl Acad Sci USA 86:1500-1503, 1989 125. Sakurai A, Shirahama S, Fujimori M, et al: Novel MENl gene mutations in familial multiple endocrine neoplasia type 1. J Hum Genet 43:199-201, 1998 126. Sano T, Asa SL, Kovacs K Growth hormone releasing-producing tumors: Clinical, biochemical and morphological manifestations. Endocr Rev 9:357-380, 1988 127. Sano T, Yamasaki R, Saito H: Growth hormone releasing hormone (GHRH)-secreting pancreatic tumor in a patient with multiple endocrine neoplasia type 1. Am J Surg Pathol 11:810-814, 1987 128. Sat0 M, Matsubara S, Miyauchi A, et al: Identification of five novel germline mutations of the MENl gene in Japanese multiple endocrine neoplasia type 1 (MENl) families. J Med Genet 35:915-919, 1998 129. Schaaf L, Gerschner M, Geissler W The importance of multiple endocrine neoplasia syndromes in differential diagnosis. Klin Wochenschr 683669473, 1990 130. Scheithauer BW, Laws ER Jr, Kovacs K, et al: Pituitary adenomas of the multiple endocrine neoplasia type 1 syndrome. Semin Diagn Pathol4205216, 1987 131. Schimke RN: Multiple endocrine neoplasia: How many syndromes? Am J Med Genet 37375383,1990 132. Shan L, Nakamura Y, Nakamura M, et al: Somatic mutations of multiple endocrine neoplasia type 1 gene in the sporadic endocrine tumors. Lab Invest 78:471475, 1998 133. Shepherd JJ: Latent familial multiple endocrine neoplasia in Tasmania. Med J Aust 142:393-397,1985 134. Sheppard BC, Norton JA, Dopmann JL, et ak Management of islet cell tumors in patients with multiple endocrine neoplasia: A prospective study. Surgery 10611081118, 1989

566

THAKKER

135. Shimizu S, Tsukada T, Futami H, et al: Germline mutations of the MENl gene in Japanese kindred with multiple endocrine neoplasia type 1. Jpn J Cancer Res 881029-1032, 1997 136. Sipple JH. The association of pheochromocytoma with carcinoma of the thyroid gland. Am J Med 31:163-166, 1961 137. Skogseid B, Oberg K, Eriksson B, et al: Surgery for asymptomatic pancreatic lesion in multiple endocrine neoplasia type I. World J Surg 20:872-877, 1996 138. Skogseid B, Rastad J, Gob1 A, et al: Adrenal lesions in multiple endocrine neoplasia type 1. Surgery 118:1077-1082, 1995 139. Skogseid B, Larsson C, Lindgren P-G, et al: Clinical and genetic features of adrenocortical lesions in multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 75:7681, 1992 140. Skogseid B, Eriksson 8, Lundqvist G, et al: Multiple endocrine neoplasia type 1: A 10-year prospective screening study in four kindreds. J Clin Endocrinol Metab 73:281-287, 1991 141. Skogseid B, Oberg K, Benson L, et al: A standardized meal stimulation test of the endocrine pancreas for early detection of pancreatic endocrine tumors in multiple endocrine neoplasia type 1 syndrome: Five years experience. J Clin Endocrinol Metab 64:1233-1240, 1987 142. Snyder N 111, Murphy TS, Deiss WP: Five families with multiple endocrine adenomatosis. Ann Intern Med 76:53-58, 1972 143. Stacpoole PW, Jaspan J, Kasselberg AG, et al: A familial glucagonoma syndrome: Genetic, clinical and biochemical features. Am J Med 701017-1026, 1981 144. Steiner AL, Goodman AD, Powers SR Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing’s disease: Multiple endocrine neoplasia, type 2. Medicine 47371407, 1968 145. Takahashi H, Nakano K, Adachi Y Multiple nonfunctional pancreatic islet cell tumor in multiple endocrine neoplasia type 1: A case report. Acta Pathol Jpn 38:667470,1988 146. Tanaka C, Kimura T, Yang P, et al: Analysis of loss of heterozygosity on chromosome 11 and infrequent inactivation of MENl gene in sporadic pituitary adenomas. J Clin Endocrinol Metab 33:2631-2634, 1998 147. Tateishi R, Wada A, Ishiguro S, et al: Coexistence of bilateral pheochromocytoma and pancreatic islet cell tumor: Report of a case and review of the literature. Cancer 42:2928-2934,1978 148. Teh BT, Esapa CT, Houlston R, et al: A family with isolated hyperparathyroidism segregating a missense MENl mutation and showing loss of the wild-type alleles in the parathyroid tumors. Am J Hum Genet 63:15&1549, 1998 149. Teh BT, Kytola S, Farnebo F, et al: Mutation analysis of the MENl gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism. J Clin Endocrinol Metab 83:2621-2626, 1998 150. Teh BT, Zedenius J, Kytola S, et al: Thymic carcinoids in multiple endocrine neoplasia type 1. Ann Surg 228:99-105, 1998 151. Teh BT, McArdle J, Chan SP, et a1 Clinicopathologic studies of thymic carcinoids in multiple endocrine neoplasia type 1. Medicine 76:21-26, 1997 152. Thakker RV Multiple endocrine neoplasia-syndromes of the twentieth century. J Clin Endocrinol Metab 83:2617-2620, 1998 153. Thakker RV Molecular genetics of parathyroid disease. Current Opinions in Endocrinology 3:521-528, 1996 154. Thakker RV Multiple endocrine neoplasia type 1 (MEN1). In DeGroot LJ, Besser GK, Burger HG, et a1 (eds): Endocrinology. Philadelphia, WB Saunders, 1995, pp 2815-2831 155. Thakker RV, Pook MA, Wooding C, et al: Association of somatotrophinomas with loss of alleles on chromosome 11 and with gsp mutations. J Clin Invest 91:2815-2821, 1993 156. Thakker RV, Bouloux P, Wooding C, et al: Association of parathyroid tumors in multiple endocrine neoplasia type 1 with loss of alleles on chromosome 11. N Engl J Med 321:218-224,1989 157. Thakker RV, Ponder BAJ: Multiple endocrine neoplasia. In Sheppard MC (ed): Clinical Endocrinology and Metabolism, vol. 2, no. 4. Molecular Biology and Endocrinology. London, Bailliere Tindall, 1988, pp 1031-1067

MULTIPLE ENDOCRINE NEOPLASIA TYPE 1

567

158. The European Consortium on MENI: Identification of the multiple endocrine neoplasia type 1 (MENI) gene. Hum Mol Genet 6:117i-1183, 1997 159. The European Consortium on MENI: Construction of a 1.2 Mb sequence-ready contig of chromosome llq13 encompassing the multiple endocrine neoplasia type 1 (MENI) gene. Genomics M94-100, 1997 160. Thompson NW. Management of pancreatic endocrine tumors in patients with multiple endocrine neoplasia type 1. Surg Oncol Clin North Am 7881491, 1998 161. Thompson MH, Sanders DJ, G m d E R The relationship of the serum gastrin and calcium concentrations in patients with multiple endocrine neoplasia type 1. Br J Surg 63:779-783, 1976 162. Tiengo A, Fedek D, Marchiori E, et al: Suppression and stimulation mechanism controlling glucagon secretion in a case of islet cell tumor producing glucagon, insulin, and gastrin. Diabetes 25:408-412, 1976 163. Toliat M-R, Berger W, Ropers HH, et al: Mutations in the MENl gene in sporadic neuroendocrine tumors of gastroenteropancreatic system. Lancet 3501223, 1997 164. Townsend CM Jr, Thompson JC: Gastrinoma. Semin Surg Oncol 691-97, 1990 165. Trump D, Farren 8, Wooding C, et al: Clinical studies of multiple endocrine neoplasia type 1 (MENI) in 220 patients. Q J Med 89653-669,1996 166. Underdahl LO, Wootner LB, Black BM Multiple endocrine adenomas: Report of 8 cases in which parathyroids, pituitary and pancreatic islets were involved. J Clin Endocrinol Metabol 13:2&47, 1953 167. Vasen HFA, Lamers CBHW, Lips CJM Screening for the multiple endocrine neoplasia syndrome type I. Arch Intern Med 149:2717-2722, 1989 168. Vemer JV,Morrison AB: Islet cell tumor and a syndrome of refractory water diarrhea and hypokalemia. Am J Med 25:374-380,1958 169. Vortmeyer AO, BOni R, Pak E, et al: Multiple endocrine neoplasia 1 alterations in MENI-associated and sporadic lipomas. J Natl Cancer Inst 90398, 1998 170. Wang EH, Ebrahimi SA, Wu AY, et a1 Mutation of the MENIN gene in sporadic pancreatic endocrine tumors. Cancer Res 58:4417-4420, 1998 171. Wermer P:Multiple endocrine adenomatosis: Multiple hormone-producing tumors, a familial syndrome. Clin Gastroenterol 3:671-684, 1974 172. Wermer P: Genetic aspects of adenomatosis of endocrine glands. Am J Med 16:363371, 1954 173. Wilkinson S, Teh BT, Davey KR, et al: Cause of death in multiple endocrine neoplasia type 1. Arch Surg 128:68?-690, 1993 174. Williams ED, Celestin LR The association of bronchial carcinoid and pluriglandular adenomatosis. Thorax 17120-127, 1962 175. Wolfe MM, Jensen RT Zollinger-Ellison syndrome: Current concepts in diagnosis and management. N Engl J Med 3171200-1209, 1987 176. Yu F, Venzem D, Serran OJ, et al: Prospective study of the clinical course prognostic factors, causes of death, and survival in patients with long-standing Zollinger-Ellison syndrome. J Cli Oncol 17:615-630, 1999 177. Zeller JR, Kauffman HM, Komorowski RA, et al: Bilateral pheochromocytoma and islet cell adenoma of the pancreas. Arch Surg 117827430, 1982 178. Zollinger Rh4, Ellison E H Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Ann Surg 142709-728, 1955 179. Zhuang Z, Ezzat SZ, Vortmeyer AO, et al: Mutations of the MENl tumor suppressor gene in pituitary tumors. Cancer Res 5754465451, 1997 180. Zhuang Z, Vortmeyer AO, Pack S, et al: Somatic mutations of the MENl tumor suppressor gene in sporadic gastrinomas and insulinomas. Cancer Res 5746824686, 1997

Address reprint requests to Rajesh V. Thakker MD, FRCF', FRCPath, FMedSci Nuffield Department of Medicine University of Oxford Level 7, John Radcliffe Hospital Headington Oxford OX3 9DU e-mail: rajesh.thakke&ndm.ox.ac.uk