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Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant tumour syndrome. It is characterized by primary hyperparathyroidism, pituitary neoplasia and foregut lineage neuroendocrine neoplasia. Malignant thymic carcinoid tumours are an uncommon but important manifestation of MEN 1. Transcervical thymectomy is often advocated as prophylaxis against thymic carcinoids, although there is a paucity of evidence to support the efficacy of this procedure. This is the first report of a malignant thymic carcinoid occurring in an MEN 1 patient following prior parathyroidectomy and transcervical thymectomy. It is concluded that transcervical thymectomy does not reliably provide prophylaxis against thymic carcinoid.

Background: The majority of reports describing the natural history and prognosis of multiple endocrine neoplasia type 1 (MEN 1) utilize phenotypic rather than molecular genetic criteria to establish a diagnosis of MEN 1., Objectives and Patients: We sought to determine the spectrum of endocrine abnormality amongst 152 members (64 gene carriers and 88 noncarriers) of a large MEN 1 family in whom a determination of MEN 1 status had previously been made by phenotype screening. The predictive utility of both clinical and molecular screening techniques are described., Results: A novel IVS2-3 (C-G) MEN1 mutation was identified in affected members of this family. Seven (10%) of 71 individuals satisfying clinical diagnostic criteria for MEN 1 were found to be genetically negative (excluded by mutation analysis and haplotyping) for MEN 1. These cases of MEN 1 phenocopy comprised four cases of primary hyperparathyroidism, two 'nonsecretory' pituitary adenoma and one case of coincident prolactinoma and hyperparathyroidism. Three of the patients with hyperparathyroidism had previously required parathyroidectomy and each had achieved normocalcaemia following parathyroid resection. Predictive genetic testing prospectively identified three children with the MEN 1 genotype. Serum calcium was normal at the time of their initial molecular genetic diagnosis. In each case hyperparathyroidism subsequently developed during adolescence., Conclusion: Multiple endocrine neoplasia type 1 phenocopy is an important differential diagnosis in patients exhibiting an multiple endocrine neoplasia type 1 phenotype. This is a relevant consideration, particularly when the diagnosis of multiple endocrine neoplasia type 1 is made using sensitive, but nonspecific, criteria such as mild hyperparathyroidism, pituitary micoadenoma, and hyperprolactinaemia. Confirmatory genetic testing should be undertaken to confirm clinical diagnoses of multiple endocrine neoplasia type 1.

Hypotheses: Preoperative parathyroid radioisotope scanning is of little or no value in patients with multiple endocrine neoplasia type 1 when 4 or more hypertrophied glands are present. Scanning using technetium Tc 99m sestamibi and single photon emission computed tomography will achieve a high level of sensitivity and specificity after 3 or more glands have previously been removed, justifying limited surgical reexploration., Design: In a prospective study, the preoperative documented report of the predicted site of residual parathyroid was compared with the surgical findings in 13 patients having 19 scans and 17 reoperations., Setting: All patients belonged to one family, previously described as Tasman family 1, and were confirmed by genetic testing as having multiple endocrine neoplasia type 1. In 10 of 13 patients, reexploration was being undertaken more than 10 years after the first operation., Main Outcome Measures: Scanning was regarded as successful when the documented preoperative report correctly predicted the side and quadrant in which a gland was found at surgery. Surgery was regarded as successful when calcium levels decreased to or below normal levels and were maintained., Results: All 13 scans before first reexploration were successful in identifying the location of a residual parathyroid. From a statistical viewpoint, this equates to 100% sensitivity and 92% specificity. However, despite accurate localization of 1 residual gland in every patient, 7 supernumerary glands in 4 patients and 1 parathyroid remnant in a fifth patient were not localized so that sensitivity in locating all glands in every patient was only 61%. Scans performed for persistent hypercalcemia 48 to 72 hours after reexploration in 2 patients were unsuccessful in demonstrating any residual parathyroid. Scans performed 3 months after surgery in the same 2 patients and a third patient were successful, with sensitivity and specificity of 100%. Apart from patient 11, who awaits reexploration, normocalcemia was eventually achieved in every patient, with 11 of 12 having an initial period of hypocalcemia., Conclusions: Three months after reexploration and trimming or resection with transplant of half a gland left at first operation, sestamibi scanning achieved sensitivity and specificity of 100% in locating supernumerary parathyroids in patients with multiple endocrine neoplasia type 1 and persistent hypercalcemia. Before first reexploration, however, scans rarely provided new information, predominantly showing only the hypertrophied half-gland remnant.

Background: Multiple endocrine neoplasia type 1 (MEN-1) is an autosomal dominant tumor syndrome associated with parathyroid, gastroenteropancreatic (GEP), and pituitary neoplasia. Gastrinoma and GEP malignancy are common life-threatening endocrine complications of MEN-1. An effective management strategy for these disorders remains to be determined. The authors attempted to determine the role of the somatostatin analogue, octreotide, in ameliorating features of hypergastrinemic GEP neoplasia associated with MEN-1., Methods: Five MEN-1 patients with hypergastrinemia and either symptoms of GEP neoplasia or hepatic metastases received a trial of octreotide, 100 microg subcutaneously, three times daily for 3 months., Results: Treatment with octreotide was associated with a rapid symptomatic and biochemical response. In all patients serum gastrin fell to < 25% of the pretreatment value. The serum glycoprotein-alphasubunit (a marker of enterochromaffin-like [ECL] cell hyperplasia, gastric carcinoidosis, and disseminated enteropancreatic malignancy) was elevated at baseline in three patients. In each case the serum glycoprotein-alphasubunit normalized after treatment with octreotide. Hepatic metastases were present in two patients at baseline. The size of the metastases diminished by up to 15% during the period of octreotide treatment. Four patients reported symptoms prior to treatment: lethargy, easy fatigability, and generalized musculoskeletal discomfort. A marked symptomatic improvement occurred in each case. No patient experienced side effects related to octreotide therapy and all elected to remain on treatment after completion of the trial., Conclusions: Octreotide is a safe and effective adjunct to surgical strategies for the management of GEP neoplasia in hypergastrinemic MEN-1 patients., (Copyright 1999 American Cancer Society.)

Background: Sporadic primary hyperparathyroidism (PHPT) occurs most frequently in postmenopausal women. Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal-dominant disease in which mild to moderate PHPT develops in most gene carriers by 20 years of age. Primary hyperparathyroidism associated with MEN 1 is typically recurrent, despite initially successful subtotal parathyroidectomy. Osteoporosis is considered a complication of sporadic PHPT and an indication for parathyroidectomy. In the setting of MEN 1, however, the relationship of bone mass to PHPT, fracture risk, and parathyroidectomy is unknown., Hypothesis: Parathyroidectomy improves bone mineral density for patients with primary hyperparathyroidism in the setting of MEN 1., Design: Case series., Setting: Tertiary referral center., Patients: Twenty-nine women with MEN 1 belonging to a single family with a history of MEN 1., Interventions: Parathyroidectomy., Main Outcome Measures: Bone mineral density (BMD) and history of skeletal fracture., Results: Osteopenia and osteoporosis were diagnosed in 41% and 45% of patients, respectively. Forty-four percent of patients with uncontrolled PHPT had severe osteopenia (T score, <-2.0) by 35 years of age. Reduction in BMD was greatest at the femoral neck. Reduced BMD was associated with an increased likelihood of skeletal fracture (P = .05). Patients with uncontrolled PHPT had lower femoral neck and lumbar spine BMDs than those in whom PHPT was controlled by parathyroidectomy (P = .005 and .02, respectively). Successful parathyroidectomy improved femoral neck and lumbar spine BMDs by a mean +/- SEM of 5.2% +/- 2.5% and 3.2% +/- 2.9%, respectively., Conclusions: Osteoporosis is a frequent and early complication of PHPT in MEN 1. Despite difficulty in achieving a cure of PHPT in MEN 1, parathyroidectomy has an important role in the optimization of BMD for patients with MEN 1.

Background: Enteropancreatic malignancy is an important cause of morbidity and mortality associated with multiple endocrine neoplasia type 1 (MEN 1). However, the risk factors and mechanisms of the tumorigenesis of this malignancy are poorly understood., Methods: The authors conducted a retrospective study of factors associated with the development of malignant enteropancreatic tumor in 69 patients with MEN 1 belonging to a single family., Results: Metastatic enteropancreatic tumor and gastrinoma were identified in 20% and 36% of patients, respectively. Compared with MEN 1 patients who did not have an immediate family history of enteropancreatic malignancy, MEN 1 patients with a first-degree relative affected by enteropancreatic malignancy had an increased risk of developing disseminated tumor (odds ratio, 3.7; P < 0.05). In addition, hypergastrinemia and advanced age were both associated with a significant increase in the risk of enteropancreatic malignancy. Elevated serum glycoprotein alpha subunit levels were associated with enterochromaffin-like cell hyperplasia, gastric carcinoid formation, and disseminated enteropancreatic tumor in hypergastrinemic patients (P < 0.05)., Conclusions: Disease modifier factors act in concert with the MEN 1 gene to modulate the development of enteropancreatic neoplasia. It is possible to identify MEN 1 patients at high risk for developing aggressive enteropancreatic tumors. Heritable disease modifier factor(s) affecting enteropancreatic malignancy appear to reside at loci distinct from that of the MEN 1 gene.

In 1983 a large family with MEN-1 (designated Tasman 1) was identified in Tasmania. Kindred screening and case follow-up over the subsequent 15 years has yielded data on over 160 MEN-1-affected patients. Hyperparathyroidism is present in over 60% of gene carriers by age 20 years and 95% by age 30 years. Hyperplasia is the characteristic pathological finding. Kaplan-Meier analysis indicates hyperparathyroidism recurs in the majority of patients despite near-total parathyroidectomy. Gastrinoma, 'nonfunctioning' pancreatic adenoma and insulinoma occur in up to 60, 50 and 10% of patients, respectively. Metastatic gastroenteropancreatic (GEP) tumours develop in up to 35% of family members, being frequent in some branches of Tasman 1, whilst rare in others. Pituitary disease developed in 19% of patients. Prolactinoma and 'nonfunctioning' adenoma account for 76 and 24%, respectively, of pituitary abnormalities. Prolactinomas exhibit clustering within branches of the Tasman 1 kindred. Adrenal adenomas occur in 36% of patients. The majority of adrenal lesions are benign and nonsecretory and develop in association with pancreatic neoplasia. Carcinoid tumours are uncommon but important malignancies. Malignant thymic carcinoid occurs in male patients, whereas bronchial carcinoid occurs predominantly in women. Prior to recognition of MEN-1 in Tasman 1, complications of hyperparathyroidism and malignancy accounted for the majority of patient mortality. Since commencement of prospective screening, malignant GEP tumours and cardiovascular disease have become the most prevalent causes of death amongst MEN-1-affected patients.

Background: The efficacy of subtotal parathyroidectomy for the treatment of hyperparathyroidism in multiple endocrine neoplasia type 1 (MEN 1) is unclear. The long-term outcome and optimal timing of operation remain controversial., Objective: To determine the long-term outcome of parathyroidectomy for primary hyperparathyroidism in the presence of MEN 1., Design: Case series and retrospective analysis., Setting: Tertiary referral center., Patients: Patients with MEN 1 from 2 families., Interventions: Subtotal parathyroidectomy, ie, resection of 3 1/2 parathyroid glands from each patient., Main Outcome Measures: Recurrence of hyperparathyroidism., Results: Thirty-seven patients underwent subtotal parathyroidectomy. Overall, persistent postoperative hypoparathyroidism developed in 24%, normocalcemia was maintained in 46%, and hyperparathyroidism recurred in 30%. However, after adjustment for the duration of follow-up (by using the Kaplan-Meier method), the cumulative recurrence rates for hyperparathyroidism were 15% at 2 years, 23% at 4 years, 55% at 8 years, and 67% after 8 years. Early recurrence of hyperparathyroidism (within 5 years of operation) was less likely to develop in patients in whom ionized calcium levels of 1.00 mmol/L (4.00 mg/dL) or less were achieved during the perioperative period than in patients in whom this degree of hypocalcemia failed to develop (P=.01)., Conclusions: While relatively long periods of disease remission are possible after subtotal parathyroidectomy, our results indicate that recurrent hyperparathyroidism eventually develops in most patients with MEN 1.

Prolactinomas and somatotropinomas are reported to be the pituitary lesions most frequently associated with multiple endocrine neoplasia type 1 (MEN 1). However, few reports have documented the full spectrum of pituitary disease in this condition. We report herein the clinical, biochemical (PRL, alpha-subunit, insulin-like growth factor-I, cortisol, and thyroid function), and radiological (magnetic resonance imaging and computerized tomography scan) characteristics of pituitary disease occurring in a single MEN 1 pedigree containing 165 MEN 1-affected members. Pituitary lesions were detected in 30 (18%) of 165 patients overall. In the subgroup of MEN 1 patients (n = 131) living after recognition of MEN 1 in the kindred, pituitary lesions were detected in 25 (19%). In 76% of patients with pituitary lesions, the diagnosis was made by prospective screening; the remainder sought medical attention for symptomatic pituitary disease. Prolactinomas accounted for 76%, and nonfunctioning adenomas accounted for the remaining 24%. alpha-Subunit elevation was observed in 29% of 41 patients tested, and an aggressive alpha-subunit secreting macroadenoma developed in 1 subject with a previously documented prolactinoma. Progression of pituitary disease occurred in 47% of patients with prolactinoma. There were no cases of Cushing's disease, thyrotropinoma, or somatotropinoma. We conclude that 1) in addition to prolactinomas, nonfunctioning pituitary tumors are common in MEN 1; 2) alpha-subunit hypersecretion is frequent in MEN 1; 3) comprehensive screening may identify many clinically significant but asymptomatic pituitary lesions; and 4) prolactinomas occurring in MEN 1 may behave more aggressively than sporadic prolactinomas.

Objective: To review the prevalence and natural history of adrenal lesions occurring in patients from a single kindred with multiple endocrine neoplasia type 1 (MEN-1)., Design: Case series., Setting: Tertiary referral center., Patients: Medical records of 33 patients from the Tasman 1 MEN-1 kindred who had undergone abdominal computed tomographic (CT) scanning were reviewed. In 30 patients, the results of abdominal ultrasonographic examinations were available for correlation with CT scan. Computed tomographic and ultrasound scans of 18 patients were reviewed by a radiologist blinded to the patients' clinical details. Three patients underwent adrenalectomy, and the histopathologic material was reviewed., Main Outcome Measures: Computed tomographic and ultrasound scans., Results: Adrenal lesions were detected in 12 patients (36%) by CT scan examination. Ultrasound imaged 58% of these lesions. Pancreatic lesions were present in all cases of adrenal disease. Follow-up was available for 8 patients with adrenal disease. Over 5.5 years, 6 patients (75%) had stable disease, 1 patient had an adrenal lesion that enlarged by 5 mm, and 1 patient had a lesion that enlarged by 50 mm. Adrenal histopathologic material was available in 3 patients. Macronodular cortical hyperplasia was present in 2 patients and a cortical adenoma present in 1 patient. Another kindred had bilateral macronodular cortical hyperplasia at autopsy., Conclusions: Adrenal lesions are common in MEN-1 and occur in association with pancreatic disease. Abdominal CT scan is more sensitive than ultrasonographic examination in detecting adrenal disease. Primary hypersecretory syndromes of the adrenal glands appear to be rare, and the majority of lesions follow an indolent clinical course.

Multiple endocrine neoplasia type 1 (MEN 1) is associated with neoplasia and hyperfunction of the parathyroid and pituitary glands, pancreatic islet cells, and neuroendocrine cells of the gut. The inheritance pattern is autosomal dominant, and the underlying genetic defect is situated at chromosome 11q13. The MEN 1 gene behaves as a defective copy of a normally constitutive tumor suppressor gene. Development of the MEN 1 phenotype, however, is a multistep and multifactorial process. The Tasman 1 genealogy is the largest MEN 1 pedigree detected to date. Thus far, 90 related members with MEN 1 have been screened for evidence of prolactinoma. Prolactinomas were found in 18 patients (20%). Prolactinomas were not evenly distributed in the genealogy; in 2 branches of the overall genealogy prolactinomas were present in 50% or more of MEN 1-affected members. The familial distribution of prolactinomas in these branches was consistent with an autosomal dominant mode of inheritance. In the remainder of the pedigree, prolactinomas were uncommon and did not display this inheritance pattern. This pedigree represents one of the largest published MEN 1 genealogies in which the risk of developing prolactinoma follows an autosomal dominant pattern of transmission. It is the first to demonstrate an inheritance pattern for prolactinomas acting in addition to, yet distinct from, the inheritance of the underlying MEN 1 gene defect. These findings are consistent with the existence of an undefined second genetic defect involved in the pathogenesis of prolactinoma in MEN 1.

Purpose: Within the spectrum of pituitary disease in multiple endocrine neoplasia type 1 (MEN-1), widely disparate prevalence rates for somatotrophinomas have been described. Studies that combine multiple, small MEN-1 kindreds report pituitary disease in 60% to 65% of patients, somatotrophinomas accounting for 27% to 37% of total pituitary lesions. However, reports based on large MEN-1 family screening programs have produced lower prevalence rates for pituitary adenomas (9% to 40%), of which somatotrophinomas comprise up to 14%. We sought to determine the prevalence of both biochemical and clinically overt growth hormone (GH) hypersecretion in the largest reported MEN-1 genealogy, the Tasman 1 kindred., Patients and Methods: The Tasman 1 MEN-1 kindred contains 165 members with established MEN-1. We reviewed the records of 124 MEN-1 patients for evidence of acromegaly or gigantism. To determine if clinical criteria underestimate the occurrence of biochemical GH hypersecretion, a subset of 33 patients was assessed for elevated levels of serum insulin-like growth factor-1 (IGF-1)., Results: No cases of acromegaly or gigantism were detected in the 124 patients reviewed. Of the 33 patients screened with IGF-1, 13 had previously diagnosed pituitary lesions--11 prolactinomas and 2 nonsecretory lesions. The IGF-1 levels were normal in all patients studied. There were no significant differences in mean IGF-1 values between patients with and without pituitary lesions., Conclusions: This report represents the largest study of growth hormone secretion patterns thus far described in MEN-1. The apparent absence of somatotrophinomas in a kindred of this size is unexpected. These results support the existence of kindred-specific MEN-1 phenotypes. We conclude that the pathogenesis of GH-secreting adenomas in MEN-1 is influenced by secondary factors acting in synergy with the well-documented primary MEN-1 gene defect on chromosome 11q13.

Background: An extensive programme was undertaken to trace and screen four known families in Tasmania with multiple endocrine neoplasia type 1 (MEN-1)., Methods: Written and personal contact was made with family members over the age of 20 years recommending a review by family practitioners for the purpose of recording their medical history and collecting a blood sample. Those suspected of MEN-1 were referred to our Department for further investigation., Results: In January 1993, the total number of individuals alive and known to be affected by MEN-1 was 107, giving a prevalence of MEN-1 disease in Tasmania of 23/100 000. The estimated prevalence of MEN-1 trait in Tasmania (including affected cases and those considered at 50% risk of possessing the trait) is 45/100 000., Conclusion: The prevalence of MEN-1 has never previously been determined accurately. The prevalence of MEN-1 in Tasmania is at the upper end of the possible range and would justify the allocation of resources for screening programmes equal to those available for the detection of several less prevalent genetic diseases.