Sporadic Multiple Endocrine Neoplasia Type 1 Research Articles

Secondary amenorrhea - an inconspicuous presentation of sporadic MEN1 syndrome

Secondary amenorrhea - an inconspicuous presentation of sporadic MEN1 syndrome

SAT180 Comparison Between Sporadic Primary Hyperparathyroidism And Multiple Endocrine Neoplasia Type 1 (MEN1)-Associated Primary Hyperparathyroidism: A Retrospective Analysis Of The Indian PHPT Registry

Abstract Disclosure: S. Bhadada: None. A.M. Chakraborty: None. P. Kumari: None. R. Pal: None. A. Sood: None. D. Dahiya: None. S.D. Rao: None. Introduction: Multiple endocrine neoplasia type 1 (MEN1)-associated tumours are located in parathyroid, pituitary and pancreatoduodenal locations. Though heterogenous, the most consistent presentation of MEN1 is primary hyperparathyroidism (PHPT) seen in almost 100% of cases. Comparisons between sporadic and MEN1 PHPT patients are sparse in the literature. Objective: To retrospectively compare the demography, clinical manifestations, management, and outcome of sporadic PHPT and MEN1-associated PHPT patients. Design and setting: A registry-based (www.indianphptregistry.com) retrospective cohort study from a tertiary care hospital in North India. Methods and patients: The medical records and clinical data of sporadic PHPT patients and MEN1-associated PHPT patients registered in the Indian PHPT registry were analysed. Result: A total of 616 PHPT patients have been registered in the electronic registry, 72 of whom (11.68%) were MEN1-associated PHPT. The mean age of sporadic PHPT patients was 43.4 ± 14.3, whereas MEN1-associated PHPT was 35.8 ± 13.5 years (p<0.05). Among MEN1-associated PHPT cases, 66 (90%) were index cases at the time of presentation, and the rest were detected on family screening. For both sporadic PHPT and MEN1-associated PHPT, the most common presenting symptom was bone pain, followed by renal stone disease. Sporadic PHPT and MEN1 PHPT both had comparable mean calcium (11.9 ± 1.5 vs 11.9 ± 1.6 mg/dl), mean phosphate (2.7 ± 1 vs 2.58 ± 0.7 mg/dl), median PTH (314; IQR 161-984 pg/ml vs 292; IQR 180-818 pg/ml) level at presentation. Median 25-hydroxyvitamin D level was 19.3; IQR 10.4-30.4 ng/dl, and 15; IQR 8.1 – 25.1 ng/dl (p<0.05) for sporadic PHPT and MEN1-associated PHPT respectively. Multiglandular disease was common in MEN1-associated PHPT (40.2%) compared to sporadic cases (3%). Median tumour weight was higher in sporadic cases (2.5; IQR 0.8- 7.3 gm) compared to MEN1 cases (1.9; IQR 1.08 – 4.05 gm). Ultrasound neck and Sesta-MIBI concordance rate among sporadic cases was 57%, whereas MEN1 cases were 70.8%. Median post-surgery decline in PTH and calcium was more in the case of sporadic PHPT in comparison to MEN1-associated PHPT 84.81% vs 46.7% and 23.4% vs 16.59 % respectively (p<0.05). Discussion: MEN1-associated PHPT patients presented at an earlier age than sporadic cases. There was no statistical difference in PTH, calcium or phosphate levels between the two cohorts, but 25-hydroxyvitamin D levels were lower in MEN1-associated PHPT. Localisation was better in the case of the MEN-1 cohort as per as the Sesta-MIBI and USG concordance was concerned. Postoperative fall of PTH and calcium was more in sporadic cases than in MEN1 cases. Presentation: Saturday, June 17, 2023

Cutaneous lesions and other non-endocrine manifestations of Multiple Endocrine Neoplasia type 1 syndrome.

Multiple Endocrine Neoplasia type 1 is a rare genetic syndrome mainly caused by mutations of MEN1 gene and characterized by a combination of several endocrine and non-endocrine manifestations. The objective of this study was to describe cutaneous lesions and other non-endocrine manifestations of MEN1 in a cohort of patients with familial (F) and sporadic (S) MEN1, compare the prevalence of these manifestations between the two cohorts, and investigate the correlation with MEN1 mutation status. We collected phenotypic and genotypic data of 185 patients with F-MEN1 and S-MEN1 followed from 1997 to 2022. The associations between F-MEN1 and S-MEN1 or MEN1 mutation-positive and mutation-negative patients and non-endocrine manifestations were determined using chi-square or Fisher's exact tests or multivariate exact logistic regression analyses. The prevalence of angiofibromas was significantly higher in F-MEN1 than in S-MEN1 in both the whole (p < 0.001) and index case (p = 0.003) cohorts. The prevalence of lipomas was also significantly higher in F-MEN1 than in S-MEN1 (p = 0.009) and in MEN1 mutation-positive than in MEN1 mutation-negative (p = 0.01) index cases. In the whole cohort, the prevalence of lipomas was significantly higher in MEN1 mutation-positive compared to MEN1 mutation-negative patients (OR = 2.7, p = 0.02) and in F-MEN1 than in S-MEN1 (p = 0.03), only after adjustment for age. No significant differences were observed for the other non-endocrine manifestations between the two cohorts. Hibernoma and collagenoma were each present in one patient (0.5%) and meningioma and neuroblastoma in 2.7% and 0.5%, respectively. Gastric leiomyoma was present in 1.1% of the patients and uterine leiomyoma in 14% of women. Thyroid cancer, breast cancer, lung cancer, basal cell carcinoma, melanoma, and colorectal cancer were present in 4.9%, 2.7%, 1.6%, 1.6%, 2.2%, and 0.5% of the whole series, respectively. We found a significantly higher prevalence of angiofibromas and lipomas in F-MEN1 compared with S-MEN1 and in MEN1 mutation-positive compared to MEN1 mutation-negative patients. In patients with one major endocrine manifestation of MEN1 , the presence of cutaneous lesions might suggest the diagnosis of MEN1 and a possible indication for genetic screening.

C-MET inhibition: novel treatment for sporadic and MEN1-associated GEP NETs.

Gastroenteropancreatic neuroendocrine tumors (GEP NETs) comprise a heterogenous and diverse group of neoplasms arising from a common neuroendocrine cell origin. The majority of these tumors occur sporadically while ~20% manifest within the context of hereditary syndromes. Germline MEN1 mutations cause a syndrome with an increased susceptibility to multifocal primary GEP NETs. In addition, somatic MEN1 mutations also occur in these sporadic lesions. MEN1 alterations are the most frequent somatic mutation found in pancreatic neuroendocrine tumors. In this review, we explore the implication of the loss of the MEN1-encoded protein menin as a key pathogenic driver in subsets of GEP NETs with downstream consequences including upregulation of the oncogenic receptor c-MET (hepatocyte growth factor receptor). Furthermore, the review will summarize the data related to the clinical presentation, therapeutic standards, and outcomes of these tumors in both sporadic and germline MEN1 mutation-associated contexts. Finally, we present the data on c-MET expression in GEP NETs, clinical trials using c-MET inhibitors and provide an overview of the molecular mechanisms by which c-MET inhibition in these lesions represents a potential precision-medicine targeted approach.

SUN-917 Aggressive De Novo MEN1 Variant in a Child with Metastatic Pancreatic Acth and Crh Co-Secreting Neuroendocrine Tumor: Diagnosis and 10-Year Follow Up

Background:In Multiple Endocrine Neoplasia type 1 (MEN1) only about 2% of pituitary adenomas are ACTH-secreting. Cushing Syndrome due to ectopic ACTH or CRH secretion from neuroendocrine tumors (NETs), carcinoid tumors, or pheochromocytomas is very rare, though patients with MEN1 are at increased risk for these three types of tumors, as well as autonomous adrenal secretion of cortisol. The 10-year follow up of a previously-reported case of a child with MEN1 and metastatic pancreatic ACTH/CRH-secreting NET is presented.Clinical Case:A previously-reported (J Clin Endocrinol Metab, 2015) now 21 yo female presented to the National Institutes of Health (NIH) at 11 yo with persistent hypercortisolemia despite transsphenoidal surgery for suspected Cushing Disease. However, the resected tissue revealed pituitary hyperplasia, and she remained hypercortisolemic. A CRH test was consistent with an ectopic source, and abdominal CT, PET scan, and Octreotide scan revealed a mass in the pancreatic tail. The patient underwent partial pancreatectomy at 11 yo with the resected tissue staining positive for ACTH and CRH. However, she remained hypercortisolemic, so bilateral adrenalectomy was performed. At 12 yo metastases were found, so Octreotide therapy was initiated. She continued to have elevated ACTH levels > 1000 pg/mL (5-46).Additionally, a pituitary adenoma was noted at 12 yo, which has since increased in size. The patient also developed mild primary hyperparathyroidism, first noted at 19 yo. Sequencing of MEN1 for the patient and her parents revealed a de novo heterozygous c.1546dupC variant, consistent with sporadic MEN1. The patient also had a chromosome 8p23.2 duplication that was present in unaffected relatives.Conclusion:While 2% of patients with MEN1 may develop Cushing Syndrome due to an ACTH-secreting pituitary adenoma, it is also important to consider ectopic secretion of ACTH/CRH from MEN1-associated NETs, carcinoid tumors, or pheochromocytomas, as well as autonomous adrenal secretion of cortisol. Given the early age and severe presentation of MEN1 features in this patient, the c.1546dupC heterozygous variant of MEN1, which has been previously reported in multiple other cases of MEN1, may represent a higher-risk causative variant of MEN1. Alternatively, expression of this variant may have been affected by the concurrent presence of an otherwise apparently benign chromosomal variant.

Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features.

The aim of this study was to carry out genetic screening of the MEN1, CDKN1B and AIP genes, both by direct sequencing of the coding region and multiplex ligation-dependent probe amplification (MLPA) assay in the largest monocentric series of Italian patients with Multiple Endocrine Neoplasia type 1 syndrome (MEN1) and Familial Isolated Hyperparathyroidism (FIHP). The study also aimed to describe and compare the clinical features of MEN1 mutation-negative and mutation-positive patients during long-term follow-up and to correlate the specific types and locations of MEN1 gene mutations with onset and aggressiveness of the main MEN1 manifestations. A total of 69 index cases followed at the Endocrinology Unit in Pisa over a period of 19 years, including 54 MEN1 and 15 FIHP kindreds were enrolled. Seven index cases with MEN1 but MEN1 mutation-negative, followed at the University Hospital of Cagliari, were also investigated. FIHP were also tested for CDC73 and CaSR gene alterations. MEN1 germline mutations were identified in 90% of the index cases of familial MEN1 (F-MEN1) and in 23% of sporadic cases (S-MEN1). MEN1 and CDC73 mutations accounted for 13% and 7% of the FIHP cohort, respectively. A CDKN1B mutation was identified in one F-MEN1. Two AIP variants of unknown significance were detected in two MEN1-negative S-MEN1. A MEN1 positive test best predicted the onset of all three major MEN1-related manifestations or parathyroid and gastro-entero-pancreatic tumors during follow-up. A comparison between the clinical characteristics of F and S-MEN1 showed a higher prevalence of a single parathyroid disease and pituitary tumors in sporadic compared to familial MEN1 patients. No significant correlation was found between the type and location of MEN1 mutations and the clinical phenotype. Since all MEN1 mutation-positive sporadic patients had a phenotype resembling that of familial MEN1 (multiglandular parathyroid hyperplasia, a prevalence of gastro-entero-pancreatic tumors and/or the classic triad) we might hypothesize that a subset of the sporadic MEN1 mutation-negative patients could represent an incidental coexistence of sporadic primary hyperparathyroidism and pituitary tumors or a MEN1 phenocopy, in our cohort, as in most cases described in the literature.

Rapid development of thymic neuroendocrine carcinoma despite transcervical thymectomy in a patient with multiple endocrine neoplasia type 1

Thymic neuroendocrine (NE) tumors are a rare manifestation of multiple endocrine neoplasia syndrome type 1 (MEN-1). They are malignant and aggressive tumors and form a major cause of mortality in MEN-1. Transcervical thymectomy (TCT) at the time of parathyroid surgery for primary hyperparathyroidism (PHPT) in MEN-1 usually prevents thymic NE tumors. We report a 56-year-old nonsmoker male with sporadic MEN-1 who presented with thymic NE carcinoma developing rapidly within a span of 8 months after subtotal parathyroidectomy and TCT for PHPT. We present a brief review of literature on this rare NE malignancy, focusing on its occurrence despite TCT. This case highlights the fact that thymic NE carcinoma may develop even after TCT in MEN-1. Regular surveillance for these aggressive thymic NE tumors is mandatory even after TCT in MEN-1 setting.

Functioning glucagonoma associated with primary hyperparathyroidism: multiple endocrine neoplasia type 1 or incidental association?

BackgroundDiagnosis of multiple endocrine neoplasia type 1 (MEN1) is commonly based on clinical criteria, and confirmed by genetic testing. In patients without known MEN1-related germline mutations, the possibility of a casual association between two or more endocrine tumors cannot be excluded and subsequent management may be difficult to plan. We describe a very uncommon case of functioning glucagonoma associated with primary hyperparathyroidism (pHPT) in which genetic testing failed to detect germline mutations of MEN-1 and other known genes responsible for MEN1.Case presentationThe patient, a 65-year old woman, had been suffering for more than 1 year from weakness, progressive weight loss, angular cheilitis, glossitis and, more recently, skin rashes on the perineum, perioral skin and groin folds. After multidisciplinary investigations, functioning glucagonoma and asymptomatic pHPT were diagnosed and, since family history was negative, sporadic MEN1 was suspected. However, genetic testing revealed neither MEN-1 nor other gene mutations responsible for rarer cases of MEN1 (CDKN1B/p27 and other cyclin-dependent kinase inhibitor genes CDKN1A/p15, CDKN2C/p18, CDKN2B/p21). The patient underwent distal splenopancreatectomy and at the 4-month follow-up she showed complete remission of symptoms. Six months later, a thyroid nodule, suspected to be a malignant neoplasia, and two hyperfunctioning parathyroid glands were detected respectively by ultrasound with fine needle aspiration cytology and 99mTc-sestamibi scan with SPECT acquisition. Total thyroidectomy was performed, whereas selective parathyroidectomy was preferred to a more extensive procedure because the diagnosis of MEN1 was not supported by genetic analysis and intraoperative intact parathyroid hormone had revealed “adenoma-like” kinetics after the second parathyroid resection. Thirty-nine and 25 months after respectively the first and the second operation, the patient is well and shows no signs or symptoms of recurrence.ConclusionsDespite well-defined diagnostic criteria and guidelines, diagnosis of MEN1 can still be challenging. When diagnosis is doubtful, appropriate management may be difficult to establish.

A novel menin gene deletional mutation in a little series of Italian patients affected by apparently sporadic multiple endocrine neoplasia type 1 syndrome

To perform a genetic screening for the multiple endocrine neoplasia type 1 (MEN1) gene mutations in patients affected by an apparently sporadic form of the disease, referred to an internal medicine unit of a large general hospital. In a group of 12 consecutive patients presenting clinical features of MEN type 1 syndrome, we performed a genetic screening for germline MEN1 gene mutations, including complete sequencing of the coding region (exons 2 to 10) and multiplex ligation-dependent probe amplification analysis for large deletion detection. Among these patients affected by apparently sporadic MEN type 1 syndrome, a targeted clinical history could detect indirect support for a diagnosis of familial condition only in 2 cases. The genetic screening identified pathogenic germline MEN1 gene mutations in 3 patients (25%). A previously unknown 18 base-pair deletion within exon 3, c.564_581delCAATGGGGAGCAGACAGC, resulting in loss of 6 amino acids (pAsp189_Ala194del), was found in heterozygosis in a woman affected by primary hyperparathyroidism and multifocal pancreatic neoplasia. Our results underscore the importance of performing genetic testing also in apparently sporadic MEN1 patients and extend the list of molecular variants leading to inactivation of the MEN1 gene.

MEN1 gene mutations in Hungarian patients with multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary disorder associated with mutations of the MEN1 gene. MEN1 may present as a familial or a sporadic disorder, with multiple endocrine tumours including parathyroid adenomas or hyperplasias, and pancreatic endocrine and pituitary gland tumours. The aim of this study was to examine the prevalence and spectrum of MEN1 gene mutations in Hungarian patients with familial and sporadic MEN1 and in those with a MEN1-related state. Mutation analysis, using temporal temperature gradient gel electrophoresis and direct sequencing of all coding exons and the corresponding exon-intron boundaries of the MEN1 gene, was performed. Peripheral blood DNA was obtained from 32 patients (19 index patients with familial or sporadic MEN1 and 13 index patients with familial or sporadic MEN1-related state). First degree relatives were also studied. Ten different MEN1 gene mutations were identified in 10 index patients, including four novel mutations (A91V, G28A and E26X all in exon 2, and L301R in exon 6). All but one mutation occurred in index patients with familial or sporadic MEN1; the prevalence of mutation was considerably higher in index patients with familial MEN1 (6/6 patients, 100%) than in those with sporadic MEN1 (3/13 patients, 23%). Of the 13 index patients with a MEN1-related state, only one patient with recurrent isolated primary hyperparathyroidism had a MEN1 gene mutation. Family screening indicated mutations in six symptomatic and in one asymptomatic first degree relative. These results confirm previous reports on the high prevalence of novel MEN1 gene mutations among patients with MEN1, and support the questionable efficacy of mutation screening in patients with sporadic MEN1-related states.

Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 1: Individualized Management With Low Recurrence Rates

To evaluate the outcomes in different surgical modalities for primary hyperparathyroidism in multiple endocrine neoplasia type 1 (MEN1) patients, intraoperative findings from a single surgeon were studied to investigate a potentially improved modality of parathyroidectomy (PTx). All 22 patients had PTx by a single surgeon in the past 21 years. Three modalities of PTx were used, depending on the operative findings, after all parathyroids and the thymus were identified. If fewer than three glands were enlarged, selective removal of the enlarged glands with or without biopsy of a normal-appearing gland was performed (selective PTx); if all glands were enlarged, either a subtotal PTx leaving a 50-mg remnant in situ or a total PTx with autotransplantation (TPTx + AT) was performed. There were 7 men and 15 women, aged 22 to 67 years (average, 43 years). Sixteen had familial and six had sporadic MEN1. They underwent 23 operations, including 11 selective PTx, 6 subtotal PTx, and 6 TPTx + AT. On follow-up for 1 to 19 years, only one patient (4.6%) had recurrent hyperparathyroidism 5.5 years after subtotal PTx. Others had either normocalcemia (n = 14; 63.6%) or hypocalcemia (n = 7; 31.8%). Those who had either a subtotal PTx or TPTx + AT had a significantly higher rate of postoperative hypocalcemia than those who had a selective PTx (9.9% vs. 54.5%; P = .032; Fisher's exact test). Primary hyperparathyroidism in our MEN1 patients was less aggressive than that reported in the literature. Selective PTx according to the intraoperative findings achieved optimal outcomes.

Multiple endocrine neoplasia type 1 (MEN1): genetic and clinical analysis in the Southern Chinese.

Multiple endocrine neoplasia type 1 (MEN1) is characterized by a triad of neoplasia affecting the parathyroid glands, enteropancreatic endocrine tissue and the anterior pituitary gland. In order to define the prevalence of MEN1 germ-line mutations in Southern Chinese patients with MEN1 syndrome, we performed direct sequencing of the entire open reading frame of the MEN1 gene for 12 index patients and their first-degree relatives. Six patients had familial MEN1 syndrome and six had apparently sporadic disease. Nine different germ-line mutations at the MEN1 gene were identified, including three novel mutations [248-249delTT in exon 2, K559X(AAG --> TAG) in exon 10 and IVS 2nt + 2(G --> T) in intron 2]. All patients with familial MEN1 syndrome were heterozygous carriers of a germ-line mutation and MEN1-related disorders were only evident in their first-degree relatives who also carried the mutation. All patients with an enteropancreatic lesion were mutation carriers and the absence of mutation in three apparently sporadic MEN1 patients with only hyperparathyroidism and pituitary microadenoma might represent the presence of MEN1 phenocopy. The finding of MEN1 germ-line mutation in all patients with familial MEN1 syndrome suggests that genetic screening should be useful in our population to identify affected individuals within a kindred and allow early detection of MEN1-related tumours.

The changing spectrum of TSH-secreting pituitary adenomas: diagnosis and management in 43 patients.

Our aim was to report the recent changes in diagnosis and management of TSH-secreting pituitary adenomas. We retrieved 43 consecutive patients with TSH-secreting pituitary tumors (23 male and 20 female) among 4400 pituitary adenomas followed between 1976 and 2001 in six Belgian and French centers. TSH was elevated in 18/43 and alpha subunit in 13/32 patients. In patients with intact thyroid (n=30), mean free tri-iodothyronine was 13.1 pmol/l (range 3.5-23) and mean free thyroxine was 38.4 pmol/l (range 10.2-62.7). Hyperprolactinemia and acromegaly were associated in 9/43 and 8/43 cases. The number of associated hypersecretions was higher in macroadenomas than in microadenomas (Chi square = 11.2, P<0.01). Two women had sporadic multiple endocrine neoplasia type 1-associated syndrome. The proportion of microadenomas versus macroadenomas was 1/11 (period 1974-1986) and 8/32 (period 1987-2001). Bilateral petrosal sinus sampling, (111)In-pentreotide scintigraphy and ((11)C)-l-methionine positron emission tomography scan confirmed diagnosis in four questionable microadenomas. Macroadenomas with extrasellar extension (31 cases) had a tendency to be medially located. Medical treatment with somatostatin analogs was initiated as first-line treatment in 26 patients. TSH levels were reduced by more than 50% in 23/26 cases. A tumoral shrinkage of more than 20% was observed in 5/13 cases. Surgery was performed in 36 patients. After 1 year, 21 of them (58.3%) met the criteria of surgical favorable outcome. Pituitary radiotherapy (n=8) and somatostatin analogs allowed normalization in cases not cured by surgery. Ultrasensitive methods for TSH measurement led to an earlier recognition of TSH-secreting pituitary tumors. In this series, we observed that TSH-secreting pituitary tumors are today more frequently found at the stage of microadenomas, medially located, without associated hypersecretions and needing new exploration methods as compared with older series. This changing spectrum in the presentation of TSH-secreting pituitary tumors and the excellent response to somatostatin analogs has been accompanied by an improvement in the prognosis of the disease.

A Novel Germline Mutation of the MEN1 Gene, L259del, in a Patient with Sporadic Multiple Endocrine Neoplasia Type 1 (MEN1)

A Japanese woman was treated for insulinoma when she was 29 years old. Ten years later, heperparathyroidism and non-functioning adrenal tumor were found and she was diagnosed as having multiple endocrine neoplasia type 1 (MEN1). No other family members have developed MEN-related lesion(s). Genomic DNA of the patient was analyzed by sequencing for the MEN1 gene and a novel, three-base in-frame deletion resulting in deletion of an amino acid Leu259 was identified. Her two children showed a wild-type sequence at this codon.

Gene diagnosis and clinical management of multiple endocrine neoplasia type 1 (MEN1)

Identification of the MEN1 gene as a disease gene for multiple endocrine neoplasia type 1 (MEN1) has made it possible to predict whether a family member of an MEN1 patient will suffer from the same disease. MEN1 mutations have been found in almost all cases with familial MEN 1, but in fewer cases with sporadic MEN1. We analyzed MEN1 mutations in the largest number of Japanese MEN1 patients, 17 families and 21 sporadic cases, and found 54 MEN1 mutant carriers and 30 non-carriers. Furthermore, we identified a MEN1 phenocopy: GH-secreting pituitary tumor and primary hyperparathyroidism, which develops at older ages. In this article, we discuss how to utilize MEN1 gene diagnostics for the clinical management of MEN 1 patients and MEN1 mutation carriers.

Sporadic endocrine tumours and their relationship to the hereditary endocrine neoplasia syndromes.

In the last years of the previous century the genes involved in the aetiology of five endocrine tumour syndromes have been identified. The tumour-suppressor gene that is responsible for Von Hippel-Lindau Disease was cloned in 1993; multiple endocrine neoplasia (MEN) types 2A and 2B and familial medullary thyroid carcinoma were found to be caused by activating mutations in the ret proto-oncogene in 1993 and 1994, and most recently the menin-gene, another tumour-suppressor gene, was shown to be associated with MEN-1. As usual, the answer to one question leads to innumerable new questions. And so, now we want to know the extent to which germ-line mutations (de novo, or otherwise previously undetected) in these genes play a role in the occurrence of the various endocrine tumours that are associated with these syndromes in apparently sporadic cases. We also want to know if the nature of the (germ-line) mutation conveys any information about the characteristics (phenotype) of the disease. We want to know the role of somatic mutations in these genes in truly sporadic tumours. And finally we want to know the exact function of the proteins that are encoded by these genes. The paper by Roijers et al. [1] elsewhere in this issue is an example of a small but well-directed step on the way to address some of these questions with respect to the menin-gene. It addresses the problem of patient selection when looking for germ-line mutations in apparently sporadic MEN-1 patients. In this review we want to give a brief summary of the present status with regard to some of the questions mentioned above, in relation to the endocrine tumour syndromes caused by the vhl, ret and menin genes.

Screening for MEN1 tumor suppressor gene mutations in sporadic pituitary tumors.

The molecular pathogenesis of the majority of sporadic pituitary tumors is largely unknown. Pituitary adenomas can develop sporadically or as a part of multiple endocrine neoplasia type 1 (MEN1). The MEN1 is thought to be a tumor suppressor gene based on loss of heterozygosity (LOH) for polymorphic markers on 11q13 in tumors of the pancreas, parathyroid, and pituitary. Most patients with familial and sporadic MEN1 carry germ-line mutations in the MEN1 gene. Two previous studies and recently a third one have analyzed mutations by sequencing the MEN1 gene in sporadic pituitary tumors but yielded conflicting results. This study was to investigate and clarify the potential role of MEN1 mutations, in sporadic pituitary adenomas. First, we examined 59 sporadic pituitary adenomas by analyzing LOH on 11q13 in the MEN1 minimal interval with microsatellite analysis. We found 3 tumors with LOH in 1 to 4 polymorphic markers in the MEN1 region. Sequencing analysis did not reveal any mutations in the coding region of the MEN1 gene. However, we found 3 polymorphisms, one of which was a novel CAC to CAT transition encoding His433His, in exon 9. The data show that while LOH occurs in some sporadic pituitary tumors, inactivating mutations of the tumor suppressor gene MEN1 are rare. These results also suggest there may be another additional tumor suppressor gene at this locus which is involved in the pathogenesis of sporadic pituitary neoplasms.

Clinical features of multiple endocrine neoplasia type 1 (MEN1) phenocopy without germline MEN1 gene mutations: analysis of 20 Japanese sporadic cases with MEN1.

Multiple endocrine neoplasia type 1 (MEN1) is a familial tumour syndrome of endocrine tumours involving parathyroids, anterior pituitary and enteropancreatic neuroendocrine tissues, and is inherited in an autosomal dominant manner with high penetrance. Recently, the gene responsible for this syndrome, MEN1, was positionally cloned from chromosome 11q13. To characterize sporadic MEN1 patients, we analysed the MEN1 gene by direct sequencing of the entire open reading frame from 20 individuals. We identified heterozygous germline mutations of the MEN1 gene in 8 of 20 (40%) cases. Seven were novel MEN1 germline mutations. Three mutations were splicing abnormalities, and all were confirmed to be splicing defects by RT-PCR. The clinical significance of detecting germline MEN1 mutations, not only in familial MEN1 but also in sporadic MEN1, was confirmed by the finding of asymptomatic mutant carriers among family members of the sporadic MEN1 patients. Seven of 8 cases with MEN1 mutations had enteropancreatic lesions in contrast to 4 of 12 (P < 0.018) in those cases with no mutation. Ten of the 12 cases without MEN1 mutation were more than 50-year-old. Six of these 10 cases had the same clinical features; primary hyperparathyroidism and a GH-secreting pituitary tumour. It is likely that the six cases without mutations were MEN1 phenocopies due to (i) two kinds of tumours with high natural incidence in older subjects developed by chance (ii) another familial tumour syndrome with low penetrance, e. g. familial acromegaly with primary hyperparathyroidism by mutation of another gene, or (iii) somatic mutation during early embryonic stages.

MEN1 gene mutations in sporadic neuroendocrine tumors of foregut derivation.

Foregut-derived neuroendocrine (NE) tumors occur sporadically or in association with multiple endocrine neoplasia type 1 (MEN1) syndrome. Thirty-nine sporadic NE tumors of foregut derivation (six thymic, 21 bronchial, three gastric, and nine pancreatic tumors) as well as two hindgut-derived rectal carcinoids for somatic MEN1 gene mutation were analyzed by direct sequencing analysis. Five tumors showed mutations: nonsense mutations (Q393X and R98X) in thymic and pancreatic NE tumors, respectively, a 4 b.p. deletion (357del4) in a gastric NE carcinoma, and missense mutations (D172Y and S178Y) in pancreatic NE tumors. No mutation was identified in pulmonary or rectal NE tumors. In a patient with a pancreatic NE tumor (D172Y), the corresponding germline DNA showed the same mutation, suggesting that sporadic MEN1 syndrome was masked in this case. Somatic MEN1 gene mutations and deletions may play a crucial role in the tumorigenesis of a subset of foregut-derived NE tumors. Sporadic MEN1 syndrome may occur as a sporadic NE tumor of the pancreas.

Identification of five novel germline mutations of the MEN1 gene in Japanese multiple endocrine neoplasia type 1 (MEN1) families.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by tumours of the parathyroid glands, the anterior pituitary, and endocrine pancreas. The MEN1 gene has recently been...