FaCD Online Syndrome Fact Sheet

Last updated: 02 Jan 2012

Name: Multiple Endocrine Neoplasia, type 1

Synonym: MEN1, Wermer disease

Mode of Inheritance: AD

OMIM number: 131100

Genes

CDKN1A/p21, mapped to 6p21.2
CDKN1B/p27, mapped to 12p13
CDKN2B/p15, mapped to 9p21
CDKN2C/p18, mapped to 1p32
MEN1, mapped to 11q13

Tumor features

adrenal adenoma
adrenocortical cancer
carcinoid of bronchus
carcinoid of thymus
collagenoma of the skin
cutaneous leiomyoma
duodenal gastrinoma
facial angiofibroma
gastrointestinal carcinoid
lipoma
meningioma
pancreatic endocrine tumor
parathyroid adenoma
pituitary adenoma
prolactinoma
thymoma

Tumor features (possible)

bronchioli, leiomyoma of the
esophageal leiomyoma
germ cell tumor, extra-gonadal
liposarcoma
melanoma, cutaneous
pancreatic adenocarcinoma
parathyroid cancer
pheochromocytoma
renal angiomyolipomas
renal cell cancer
schwannoma (neurilemmoma), peripheral nerve
seminoma
spinal cord ependymoma
testicular teratoma
thyroid cancer, follicular
thyroid cancer, medullary
thyroid cancer, papillary
uterine leiomyoma

Non-tumor features

hyperparathyroidism

Comment

This disorder is characterized by hyperparathyroidism (85-97 % of MEN 1 cases; parathyroid hyperplasia and adenomas (multiple in 16 %), endocrine tumors of the pancreas (30-82 %), pituitary adenomas (30 to more than 60%), duodenal and gastric gastrinomas (25 %), adrenocortical lesions (10-40 %) and carcinoids of the thymus, bronchus and gastrointestinal tract (especially stomach and duodenum) (5-9%)[1-8]. The complete classic triad of hyperparathyroidism, pancreatic endocrine tumor and pituitary adenoma is present in about 10-12 % of MEN 1 cases[2;3]. Parathyroid cancer is very rare in this syndrome[38]. Plurihormonal pituitary adenomas have been shown to be more frequent in MEN1 tumors than in pituitary adenoma patients without MEN1[31]. The combination of hyperparathyroidism and pancreatic tumors are found in 19 -26% of MEN 1 cases, hyperparathyroidism and pituitary adenomas in 14 % of cases[2;3]. Hyperparathyroidism is the first clinical manifestation of MEN 1 in the vast majority of patients. About 60 % of MEN 1 patients have become symptomatic before the age of 40; by periodic screening, 60 % is identified before the age of 25[2].

Approximately 99 % of hyperparathyroidism is not due to MEN 1, however, if it occurs before the age of 50 and/or the lesions are hyperplastic or multiglandular, then the risk of MEN 1 is approximately 10 %[3]. Corbetta et al.[9] showed a prevalence of approximately 5 % of primary hyperparathyroidism in unselected patients with pituitary gland tumors. In patients with prolactinomas this percentages rose to approximately 14 %. Approximately 10-60 % of pancreatic endocrine tumors occur in the setting of MEN 1[3] and 10-38 % of patients with Zollinger-Ellison syndrome (caused by gastrinomas) have MEN 1[3]. Duodenal microgastrinomas are the cause of ZES in most MEN 1 patients[4]. The gastric carcinoids associated with MEN1 are ZES associated and referred to as type II (enterochromaffin-like (ECL) cell carcinoids)[10]. Up to 17-25 % of patients with a carcinoid of the thymus have MEN 1[11;12]. Thymic carcinoids in MEN1 are not associated with Cushing or carcinoid syndrome; local invasion, distant metastasis and recurrence are common[12]. Among the pituitary tumors in MEN 1, prolactinomas and somatotropic hormone producing tumors are the most frequent, gonadotropic or thyrotropic adenomas are relatively rare[4,13]. Adrenocortical changes are not rare in MEN 1; diffuse or nodular hyperplasia or (multiple) adenomas are the common lesions, of which the majority is endocrinologically silent[4,14,15]. Adrenocortical cancer is relatively rare[14,24,37] and occurs in 2%-6% of cases[37].

MEN 1 associated pancreatic endocrine tumors have a lower malignancy rate than sporadic tumors. Still, MEN1 patients with a first-degree relative with an enteropancreatic malignancy have an increased risk of developing disseminated tumors[16]. Gastrinomas are the most frequent MEN 1 pancreatic endocrine tumors, but glucagonomas, insulinomas, vipomas, somatostatinomas, PPomas and others have been detected as well[3,17]. Ductal adenocarcinomas of the pancreas (occurring as early as 32 years) have been reported in a few MEN1 patients and appear to be a rare complication[18]. The malignancy rate of duodenal gastrinomas in MEN 1 is approximately 60 %. The MEN 1 associated thymic carcinoids may be pigmented (as in melanomas) and are predominantly asymptomatic until a very late stage[19]. Cutaneous tumors ( facial angiofibromas, collagenomas, and lipomas) may also occur in MEN 1[20,32,34] and molecular studies (LOH of the MEN1 locus) strongly suggested that these tumors truly belong to the disease spectrum[21]. Multiple gingival papules and hypopigmented macules have been reported as well[20]. Lipomas may also have a visceral location. Leiomyomas at various anatomical sites appear to be associated with MEN1 as well[25,3].

Some other tumors have been reported as rare and possibly coincidental findings in MEN 1[8]: (bilateral) renal cell cancer[22;23] liposarcoma (REF), follicular-, papillary and even medullary thyroid carcinoma (REF), ], pheochromocytoma[2], malignant melanoma[2], testicular teratoma[2], mediastinal seminoma[35], peripheral nerve schwannoma[24], spinal cord ependymoma[24] and meningioma[30]. The gene mutated in the germline in MEN 1 was finally cloned in 1997[26]. Stock et al.[27] reported a family with pituitary tumors (associated with acromegaly and hyperprolactemia) and relatively few cases of hyperparathyroidism, which did not show linkage with the MEN1 locus.

Criteria[28]: the presence of tumors from 2 or more categories (a-c) typically associated with MEN1:

a) parathyroid gland tumor
b) enteropancreatic neuroendocrine tumor
c) pituitary gland tumor
(one could also consider including d) duodenal gastrinomas)

To increase the detection rate (up to more than 50%) of germline MEN1 mutations in patients with apparently sporadic tumors from the MEN1 tumor spectrum, criteria have been formulated for MEN 1-suspected patients[29]:

Young age at onset (<35 years) and/or
multiple related MEN-1 tumors in a single organ, or
2 organs affected

Tumors counted as MEN-1 related in these criteria: tumors of the parathyroid glands, endocrine pancreas, anterior pituitary gland, adrenal gland and neuroendocrine carcinoid tumors.

Germline mutations in the MEN1 gene cause this syndrome. In a minority of MEN1 and MEN1-like families no germline MEN1 mutations but rare germline mutations in Cyclin-Dependent Kinase Inhibitor Genes p15, p18, p21 and p27 have been detected[36]. See also MEN4.

Links

eMedicine info on MEN 23 1 08

References