Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released - Under Revision 1.1.0
• GENE/GENE PANEL: MEN1
• Condition: Multiple Endocrine Neoplasia Type I
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• MEN1 ⇔ 131100: Assertion Pending

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity from parathyroid adenoma / Biochemical surveillance	1	3C	3B	3	10CB
Morbidity from other neuroendocrine tumors / Biochemical surveillance	2	3C	2B	3	10CB
Morbidity from other neuroendocrine tumors / Imaging surveillance	2	3C	2B	2	9CB

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Multiple Endocrine Neoplasia type 1 (MEN1) has an estimated prevalence of 1/10,000 to 1/30,000. [1, 2]

Clinical Features

MEN1 syndrome includes varying combinations of more than 20 endocrine and non-endocrine tumors. Associated endocrine tumors including parathyroid tumors, anterior pituitary tumors, well-differentiated endocrine tumors of the gastro-entero-pancreatic tract, carcinoid tumors, and adrenocortical tumors. Parathyroid tumors, resulting in primary hyperparathyroidism, are the most common feature of MEN1. Clinical features are related to the sites of the tumors and their products of secretion. Non-endocrine tumors include facial angiofibromas, collegenomas, lipomas, meningiomas, edendymomas, and leiomyomas. [1, 2, 3]

Natural History

Parathyroid tumors, resulting in primary hyperparathyroidism, are the most common feature and the first clinical manifestation in 90% of individuals with MEN1 with onset typically between ages 20 and 25 years. However MEN1 affects all age groups, with a reported age range of 5 to 81 years. Untreated patients with MEN1 have a decreased life expectancy with a 50% probability of death by age 50. The cause of death in 50-70% of cases due to a malignant tumor process or sequelae of the disease. MEN1-associated tumors are more difficult to treat surgically, are more associated with occult metastatic disease, and may be larger, more aggressive, and more resistant to treatment than non-MEN1 associated tumors. MEN1 affects both sexes equally. [1, 3]

2. How effective are interventions for preventing harm?

Patient Management

Prophylactic thymectomy should be considered at the time of neck surgery for primary hyperparathyroidism in males with MEN1 syndrome, particularly those who are smokers or have relatives with thymic carcinoid. (Tier 3) [2]

Surveillance

Patients with MEN1 should undergo a program of combined clinical, biochemical, and radiological screening for MEN1-associated tumors. Patients are recommended to undergo screening for parathyroid tumors with an annual assessment of plasma calcium and parathyroid hormone to screen for primary hyperparathyroidism beginning at age 8. Patients are also suggested to undergo additional screening for pancreatic NET, pituitary tumors, thymic NET, bronchopulmonary NET, gastric NET, and adrenal tumors. The nature and timing of the screening will depend on local resources, clinical judgment, and patient preferences. The prognosis for MEN1 patients might be improved by presymptomatic tumor detection as earlier diagnosis and treatment of these tumors may help reduce morbidity and mortality. (Tier 2) [3]

Circumstances to Avoid

Information on circumstances to avoid was not available.

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

The prevalence of MEN1 is estimated at 1/30,000.
Given that MEN1 mutations are detected in 80-90% of probands with familial MEN1 it is expected that the mutation frequency would also approach 1/30,000. (Tier 3) [2]

Penetrance

The age-related penetrance for all clinical features of MEN1 surpasses 50% by age 20 and 95% by age 40. (Tier 3) [2]

For specific tumor types, penetrance estimates are: parathyroid adenoma (90%), enteropancreatic tumor (30-70%), pituitary adenoma (30-40%), adrenal cortical tumor (40%), pheochromocytoma (< 1%) , bronchopulmonary NET (2%), thymic NET (2%), gastric NET (10%), lipomas (30%), angiofibromas (85%), collagenomas (70%), and meningiomas (8%). (Tier 3) [2]

Relative Risk

Information on relative risk of MEN1 tumors was not available.

Expressivity

Combinations of affected glands and their respective pathological features may differ in members of the same family and even between identical twins. (Tier 3) [2, 3]

4. What is the Nature of the Intervention?

Nature of Intervention

The identified interventions involve a complex program clinical, biochemical, and radiological screenings which may be burdensome and involve risks.

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Given the early age of tumor development and recommended screenings that are not a part of typical recommended clinical care, patients with MEN1 would likely escape detection prior to symptoms indicative of endocrine tumors. [2, 3]

Date of Search: 06.04.2015

Reference List

1. Multiple endocrine neoplasia type 1. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=652

2. F Giusti, F Marini, ML Brandi. Multiple Endocrine Neoplasia Type 1. 2005 Aug 31 [Updated 2015 Feb 12]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1538

3. Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F, Brandi ML. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. (2012) 97(9):2990-3011.