Medical genetics: advances in brief: Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A

Germ line mutations of the multiple endocrine neoplasia type 1 (MEN1) tumour suppressor gene cause MEN1, a rare familial tumour syndrome associated with parathyroid hyperplasia, adenoma and hyperparathyroidism (HP). Here we investigated the role of the MEN1 gene in isolated sporadic and familial HP. Using RT-PCR single-strand conformational polymorphism screening, somatic (but not germ line) mutations of the MEN1 coding sequence were identified in 6 of 31 (19.3%) adenomas from patients with sporadic primary HP, but none in patients (n=16) with secondary HP due to chronic renal failure. MEN1 mutations were accompanied by a loss of heterozygosity (LOH) for the MEN1 locus on chromosome 11q13 in the adenomas as detected by microsatellite analysis. No DNA sequence divergence within the 5' region of the MEN1 gene, containing the putative MEN1 promoter, was detectable in HP adenomas. Clinical characteristics were not different in HP patients with or without MEN1 mutation. Heterozygous MEN1 gene polymorphisms were identified in 9.6% and 25% of patients with primary and secondary HP respectively. In a large kindred with familial isolated familial HP, MEN1 germ line mutation 249 del4 and LOH was associated with the HP phenotype and a predisposition to non-endocrine malignancies. We suggest that the bi-allelic somatic loss of MEN1 wild-type gene expression is involved in the pathogenesis of a clinically yet undefined subset of sporadic primary HP adenomas. MEN1 genotyping may further help define the familial hyperparathyroidism-MEN1 disease complex, but it seems dispensable in sporadic primary HP.

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Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A

Nature ◽

10.1038/363458a0 ◽

1993 ◽

Vol 363 (6428) ◽

pp. 458-460 ◽

Cited By ~ 1213

Author(s):

Lois M. Mulligan ◽

John B. J. Kwok ◽

Catherine S. Healey ◽

Mark J. Elsdon ◽

Charis Eng ◽

...

Keyword(s):

Multiple Endocrine Neoplasia ◽

Multiple Endocrine Neoplasia Type ◽

Germ Line ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type ◽

Germ Line Mutations

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Germ Line Mutations of the ret Proto-oncogene in Japanese Patients with Multiple Endocrine Neoplasia Type 2A and Type 2B

Japanese Journal of Cancer Research ◽

10.1111/j.1349-7006.1994.tb02962.x ◽

1994 ◽

Vol 85 (9) ◽

pp. 879-882 ◽

Cited By ~ 8

Author(s):

Shoichi Maruyama ◽

Toshihide Iwashita ◽

Tsuneo Imai ◽

Hiroomi Funahashi ◽

Isabella Ceccherini ◽

...

Keyword(s):

Multiple Endocrine Neoplasia ◽

Multiple Endocrine Neoplasia Type ◽

Germ Line ◽

Japanese Patients ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type ◽

Germ Line Mutations

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Absence of Germ-Line Mutations of the Multiple Endocrine Neoplasia Type 1 (MEN1) Gene in Familial Pituitary Adenoma in Contrast to MEN1 in Japanese

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.83.3.960 ◽

1998 ◽

Vol 83 (3) ◽

pp. 960-965 ◽

Cited By ~ 24

Author(s):

C. Tanaka

Keyword(s):

Pituitary Adenoma ◽

Multiple Endocrine Neoplasia ◽

Multiple Endocrine Neoplasia Type ◽

Germ Line ◽

Men1 Gene ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type ◽

Germ Line Mutations

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Absence of Germ-Line Mutations of the Multiple Endocrine Neoplasia Type 1 (MEN1) Gene in Familial Pituitary Adenoma in Contrast to MEN1 in Japanese1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.83.3.4653 ◽

1998 ◽

Vol 83 (3) ◽

pp. 960-965

Author(s):

Chisato Tanaka ◽

Katsuhiko Yoshimoto ◽

Shozo Yamada ◽

Hiroshi Nishioka ◽

Setsuko Ii ◽

...

Keyword(s):

Pituitary Adenoma ◽

Multiple Endocrine Neoplasia ◽

Multiple Endocrine Neoplasia Type ◽

Germ Line ◽

Men1 Gene ◽

Men 1 ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type ◽

Germ Line Mutations

Germ-line mutations of the MEN1 gene were analyzed in five cases of familial and four cases of sporadic multiple endocrine neoplasia type 1 (MEN-1), six cases in three independent pedigrees of familial pituitary adenoma without MEN-1, and three cases of familial isolated primary hyperparathyroidism (FIHP) in Japanese. Eight different types of germ-line mutations in all nine cases of MEN-1 were distributed in exons 2, 3, 7, and 10 and intron 7 of the MEN1 gene. Loss of heterozygosity (LOH) on 11q13 was detected in all nine tumors of these cases with microsatellite analysis. No germ-line mutation of the MEN1 gene was detected in three pedigrees of familial pituitary adenoma and three cases of FIHP. LOH on 11q13 was detected in two cases in one pedigree of familial pituitary adenoma, and one of them showed a heterozygous somatic mutation of the MEN1 gene. No LOH on 11q13 was detected in three cases of FIHP. Based on these, we conclude that the loss of function of menin is etiological for familial or sporadic MEN-1, but not for FIHP or most familial pituitary adenoma without MEN-1.

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Pancreatitis as the first manifestation of multiple endocrine neoplasia type 2A

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302008000800021 ◽

2008 ◽

Vol 52 (8) ◽

pp. 1332-1336 ◽

Cited By ~ 1

Author(s):

José Miguel Dora ◽

Débora Rodrigues Siqueira ◽

Erika L. Souza Meyer ◽

Márcia Khaled Puñales ◽

Ana Luiza Maia

Keyword(s):

Primary Hyperparathyroidism ◽

Multiple Endocrine Neoplasia ◽

Medullary Thyroid Cancer ◽

Multiple Endocrine Neoplasia Type ◽

Germ Line ◽

Ulcer Disease ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type ◽

Associated Conditions ◽

Germ Line Mutation

Multiple endocrine neoplasia type 2A (MEN2A) is an autosomal dominant inherited condition that predisposes to the triad of medullary thyroid cancer (MTC), pheochromocytoma (Pheo), and primary hyperparathyroidism (PHT). Nearly 100% of MEN2A are associated with germ line mutation of the RET proto-oncogene (RET), and DNA-based RET genotype analysis is now considered essential for earlier diagnosis. The first manifestation of MEN2A is most often due to MTC, and less frequently to Pheo. Rarely, MEN2A is recognized during the search for PHT associated conditions. Most patients with primary hyperparathyroidism are asymptomatic, and the focus of the presentation may be the side effects of chronic hypercalcemia, osteoporosis, renal lithiasis, peptic ulcer disease, and hypertension. Hypercalcemic pancreatitis is rare, being an uncommon first manifestation of PHT. Here, we report on a patient who presented recurrent pancreatitis as the first manifestation of MEN2A. In the present case, prompt sequential dosage of calcium, diagnosis of PHT, and genetic analysis would have resulted in pancreatitis prevention and early MEN2A management.

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Germ Line Mutation in the RET Proto-oncogene Associated with Familial Multiple Endocrine Neoplasia Type 2B: A Case Report

Japanese Journal of Clinical Oncology ◽

10.1093/oxfordjournals.jjco.a039752 ◽

1995 ◽

Keyword(s):

Case Report ◽

Multiple Endocrine Neoplasia ◽

Multiple Endocrine Neoplasia Type ◽

Germ Line ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type ◽

Germ Line Mutation

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Two familial giant pituitary adenomas associated with overweight: clinical, morphological and genetic features

Acta Endocrinologica ◽

10.1530/eje.0.1440227 ◽

2001 ◽

pp. 227-235 ◽

Cited By ~ 10

Author(s):

E Ferretti ◽

ML Jaffrain Rea ◽

C Asteria ◽

D Di Stefano ◽

V Esposito ◽

...

Keyword(s):

Pituitary Adenomas ◽

Multiple Endocrine Neoplasia ◽

Multiple Endocrine Neoplasia Type ◽

Germ Line ◽

Somatostatin Analogues ◽

High Serum ◽

Giant Pituitary Adenoma ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type

OBJECTIVE: Pituitary adenomas are usually sporadic, although rare familial cases have been described. Here we report two first degree female cousins with giant pituitary adenoma and overweight. Both presented with secondary amenorrhoea, occasional headache and weight gain. MATERIALS AND METHODS: In both patients clinical, morphological and genetic studies were performed. Both patients underwent surgery and post-operative medical therapy with somatostatin analogues and dopamine agonist, followed by a conventional radiotherapy course. RESULTS: Clinical examination at presentation revealed an acromegaloid habitus only in the second patient. Basal and dynamic hormonal evaluation showed high serum GH and serum IGF-I values, higher in the second than in the first patient, and a mild hyperprolactinaemia only in the first patient. On optical and electron microscopy, both tumours were oncocytic adenomas, immunopositive for GH in the first patient and GH/prolactin in the second. The genetic analysis for germ-line mutations of the multiple endocrine neoplasia type 1 gene was negative. Two years after radiotherapy a remarkable shrinkage of both tumours was observed, whereas the overweight worsened in both patients, accompanied by high plasma leptin values. CONCLUSION: To our knowledge, this is the first report of familial pituitary adenomas including one case of a clinically silent GH-secreting adenoma. In addition, it provides further evidence that familial pituitary tumours can occur as a multiple endocrine neoplasia type 1 unrelated disease.

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