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GeneDx, Inc.
207 Perry Parkway
Gaithersburg, MD 20877
Phone: 301-519-2100
Fax: 301-519-2892
E-mail: [email protected]
www.genedx.com
Test Information Sheet
Menin Gene Analysis in Multiple Endocrine Neoplasia Type 1 and
Familial Isolated Hyperparathyroidism (FIHP)
Also known as: MEN1; Endocrine adenomatosis, multiple; MEA I; Wermer syndrome; Menin; Familial Isolated
Hyperparathyroidism; FIHP; Hyperparathyroidism 1; HRPT1.
Mendelian Inheritance in Man Number: 113110 (both Multiple endocrine neoplasia, type 1 disease and MEN1 gene);
145000 (Familial Isolated Hyperparathyroidism)
Clinical features:
Multiple endocrine neoplasia type 1 (MEN1) is characterized by endocrine tumors, particularly in the parathyroid
glands, anterior pituitary, and pancreatic islet cells.1,2 Primary tumors may be found in more than one endocrine organ
and/or multiple tumors may be found in the same organ. Adrenal tumors, including pheochromocystomas, have also
been reported in individuals with MEN1.3,4 MEN1-associated endocrine tumors cause an array of clinical and
biochemical manifestations secondary to hormone hypersecretion: hyperparathyroidism (the most frequent MEN1symptom with potential effects on the central nervous system (CNS), hypercalcemia, gastrointestinal, renal
cardiovascular, and skeletal involvement), hypercortisolism, gigantism and acromegaly, prolactinoma (with associated
oligomenorrhea, amenorrhea, and galactorrhea in females and sexual dysfunction in males), gastrinoma, and
insulinoma.1 Non-endocrine tumors also are common and can include facial angiofibromas and collagenomas of the
skin, lipomas, meningioma and ependymoma of the CNS, and leiomyomas.1,2 MEN1 is caused by pathogenic variants
in the menin gene (MEN1), which are highly penetrant. Approximately 50% of MEN1 variant carriers are
symptomatic by age 20 and 95% are symptomatic by the age of 40.1
Familial Isolated Hyperparathyroidism (FIHP), a disorder characterized by parathyroid adenoma/hyperplasia (and
possibly carcinoma) in the absence other associated endocrinopathies, is also associated with pathogenic variants in
the MEN1 gene.1,2 However, FIHP is genetically heterogeneous and can be caused by pathogenic variants in other
genes, such as CASR and HRPT2, for which genetic testing also is available at GeneDx.
Inheritance pattern: MEN1: Autosomal dominant; 10% of cases result from de novo variants1,2,5
FIHP: Autosomal dominant
Reasons for referral:
1. Confirmation of a clinical diagnosis
2. To differentiate MEN1-related FIHP from other causes (variants in CASR or HRPT2 genes)
3. Identification of at-risk family members
4. To determine appropriate surveillance and treatment protocols
5. Genetic counseling
6. Prenatal diagnosis
Test method:
Using genomic DNA of the submitted specimen, bi-directional sequencing analysis of the coding regions (exons 2-10)
and all splice junctions, including that of non-coding exon 1, of the MEN1 gene is performed. Variants found in the
first person of a family to be tested are confirmed by repeat analysis using sequencing, restriction fragment analysis,
or another appropriate method. If no variant is found by sequencing, multiplex ligation-dependant probe
amplification (MLPA) is available to evaluate for a deletion or duplication of one or more exons of this gene.
Test sensitivity:
Multiple endocrine neoplasia type 1
Germline MEN1 variants have been found in 65-90% of patients with a clinical diagnosis of MEN1, regardless of
family history.2,5 Of patients who do not harbor a variant identifiable on sequencing, it is estimated that 1-8% of
patients with familial MEN1 will have a heterozygous partial or whole deletion of the MEN1 gene.2,6,7,8 Although the
sequencing approach used by GeneDx is expected to identify >99% of existing small intragenic variants in the MEN1
Information Sheet on Multiple Endocrine Neoplasia Type 1
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GeneDx Revision Date: 12/2015
gene, this method will miss a partial or whole gene deletion. Therefore, if indicated, MLPA analysis is available to
screen for such deletions.
Familial Isolated Hyperparathyroidism (FIHP)
Based on three studies, 23%-57% of patients with clinically diagnosed FIHP are expected to have a variant in the
MEN1 gene. 9, 10
Variant spectrum:
Over 400 different variants have been identified in the 9 coding exons of the MEN1 gene. Small deletions, small
insertions, and nonsense changes constitute the majority of variants. Most variants in MEN1 result in premature
truncation of the predicted protein; however, missense changes and, less frequently, partial/whole deletions have been
detected. Individuals with FIHP are significantly more likely to have a missense pathogenic variant in the MEN1 gene
than those with a diagnosis of MEN1.1,2
Specimen Requirements and Shipping/Handling:
 Blood: A single tube with 1-5 mL whole blood in EDTA. Ship overnight at ambient temperature, using a cool
pack in hot weather. Specimens may be refrigerated for 7 days prior to shipping.
 Buccal Brushes: We cannot accept buccal brush specimens for MEN1 analysis.
 Prenatal Diagnosis: For prenatal testing for a known pathogenic variant in the MEN1 gene, please refer to the
specimen requirements table on our website at: http://www.genedx.com/test-catalog/prenatal/. Ship specimen
overnight at ambient temperature, using a cool pack in hot weather.
Required Forms:
 Sample Submission (Requisition) Form – complete all pages
 Payment Options Form or Institutional Billing Instructions
For test codes, prices, CPT codes, and turn-around-times, please refer to the
“Multiple Endocrine Neoplasia Type 1” page on our website: www.genedx.com.
Possible ICD-10 Codes:
Benign neoplasm of other endocrine glands: D35.9
Benign neoplasm of parathyroid gland: D35.1
Benign neoplasm of pituitary gland: D35.2
Benign neoplasm of craniopharyngeal duct: D35.3
References Cited: 1. Thakker RV et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 97: 2990-3011,
2012; 2. Giusti F, Marini F, Brandi ML. Multiple Endocrine Neoplasia Type 1. 2005 Aug 31 [Updated 2015 Feb 12]. In: Pagon RA, Adam MP, Ardinger HH, et
al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. Available from:
http://www.ncbi.nlm.nih.gov/books/NBK1538/; 3. Langer P et al. Adrenal involvement in multiple endocrine neoplasia type 1. World J Surg, 26: 891-896, 2002;
4. Denes J et al. Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient
cohort. J Clin Endocrinol Metab, 100: E531-541, 2015; 5. Brandi ML et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol
Metab, 86: 5658-5671, 2001; 6. Bergman L et al. Identification of MEN1 gene mutations in families with MEN1 and related disorders. Br J Cancer, 83: 10091014, 2000; 7. Cavaco BM et al. Mutational analysis of Portugese families with multiple endocrine neoplasia type 1 reveals large germline deletions. Clin
Endocrinol (Oxf), 56: 465-73, 2002; 8. Klein RD et al. Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. Genet Med, 7:
131-8, 2005; 9. Villablanca, A. et al. Involvement of the MEN1 locus in familial isolated hyperparathyroidism. Eur J Endocrinol. 147: 313-322, 2002; 10.
Pannett, AA. et al. Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated primary hyperparathyroidism. Clin Endocrinol. 58:639646, 2003.
Information Sheet on Multiple Endocrine Neoplasia Type 1
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GeneDx Revision Date: 12/2015