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
• Status (Pediatric): Incomplete (Consensus scoring is Incomplete)
• GENE/GENE PANEL: RET
• Condition: Multiple Endocrine Neoplasia Type IIB
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• RET ⇔ 162300: 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
Prophylactic thyroidectomy / Medullary thyroid carcinoma	2	3C	3A	1	9CA
Biochemical surveillance / Pheochromocytoma	2	3C	3B	3	11CB

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

Prevalence of the Genetic Condition

Altogether multiple endocrine neoplasia type 2 (MEN2) subtypes (MEN2A, MEN2B, and familial medullary thyroid cancer or FMTC) affect 1/30,000 to 1/35,000 individuals. MEN2B constitutes roughly 5% of MEN2 cases. However, the prevalence of MEN2B specifically is unknown. [1, 2, 3]

Clinical Features

MEN2B is associated with an increased risk for medullary thyroid carcinoma (MTC) and pheochromocytoma (PHEO). In contrast to MEN2A, MEN2B is not associated with an increased risk for hyperparathyroidism. MEN2B is also associated with developmental features including mucosal neuromas, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and marfanoid body habitus. [1, 2, 3, 4, 5]

Natural History

MTC in individuals with MEN2 typically presents at a younger age than sporadic MTC and is more often associated with C-cell hyperplasia as well as multifocality or bilaterality. In MEN2B, all individuals will develop an aggressive form of MTC at an early age, typically during infancy or early childhood. Individuals with MEN2B who do not undergo thyroidectomy prior to age 1 will develop metastatic MTC at an early age. Without thyroidectomy, the average age of death for those with MEN2B is age 21. PHEOs occur in only 50% of individuals, but 50% of those are multiple and often bilateral. MEN2B, individuals may be identified in infancy or early childhood by the presence of mucosal neuromas and a distinctive facial appearance. [1, 2, 3, 4, 5]

2. How effective are interventions for preventing harm?

Patient Management

All patients with MEN2 should undergo prophylactic thyroidectomy. The recommended timing of surgery is based on a classification system of RET codon mutations and other indicators of risk for aggressive MTC. RET mutations associated with MEN2B are classified as "highest risk" and are recommended to undergo thyroidectomy in the first year of life. The goal of early prophylactic thyroidectomy is to intervene before metastasis, which is associated with a low cure rate. Evidence for the effectiveness of this intervention among MEN2B patients specifically was not provided. In 2 follow-up studies of MEN2 patients who had undergone thyroidectomy, there were no signs of MTC in 41/46 MEN2A/FMTC patients after an average period of 7 years and in 44/50 MEN2A patients after 10 years, showing that detection and intervention of MTC can significantly alter associated morbidity. (Tier 1) [2, 6]

Surveillance

PHEO surveillance should include annual plasma free metanephrines and normetanephrines or 24-hour urine collection for metanephrines and normetanephrines. Based on typical age of PHEO onset, surveillance is recommended to begin at age 11 for MEN2B. (Tier 2) [2, 6]

Because of the high risk to the fetus and mother, the presence of a PHEO must be excluded in women with MEN2B who are planning a pregnancy or are pregnant. (Tier 2) [2, 6]

Circumstances to Avoid

Use of liraglutide or similar drugs for diabetes is contraindicated in patients with MEN2. Testing in animal studies has been associated with the development of thyroid C-cell tumors, although the relevance in humans is unknown. (Tier 2) [7, 8]

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

Mode of Inheritance

Autosomal Dominant [5]

Prevalence of Genetic Variants

RET mutations are identified in at least 98% of MEN2B cases. Information on the frequency of RET mutations associated with MEN2B was not available. (Tier 3) [5]

Penetrance

The frequencies of associated outcomes are: 100% MTC, 50-60% PHEO, 100% neuromas, 60% megacolon, and 60-80% marfanoid habitus. PHPT is rare. (Tier 3) [2, 3, 5]

Penetrance of MTC: 100% (Tier 3) [2, 3, 5]

Penetrance of PHEO: 50-60% (Tier 3) [2, 3, 5]

Relative Risk

Information regarding relative risk was not available.

Expressivity

Patients carrying the same mutation may show a heterogeneous progression of disease. Even within the same family, the natural course of disease may vary. (Tier 2) [3]

4. What is the Nature of the Intervention?

Nature of Intervention

The recommendations included in this report include prophylactic thyroidectomy, an invasive surgery associated with potential risk, as well as regular biochemical screening which could be burdensome.

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

Chance to Escape Clinical Detection

MTC in individuals with MEN2B is more aggressive and presents at a much earlier age than sporadic MTC and would be highly likely to escape clinical detection in the setting of recommended clinical care. (Tier 3) [5]

Date of Search: 06.04.2015

Reference List

1. Multiple endocrine neoplasia type 2B. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=247709

2. Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, Moley JF, Pacini F, Ringel MD, Schlumberger M, Wells SA Jr. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. (2009) 19(6):565-612.

3. Niederle B, Sebag F, Brauckhoff M. Timing and extent of thyroid surgery for gene carriers of hereditary C cell disease--a consensus statement of the European Society of Endocrine Surgeons (ESES). Langenbecks Arch Surg. (2014) 399(2):185-97.

4. Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA Jr, Marx SJ. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. (2001) 86(12):5658-71.

5. 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

6. Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, Pacini F, Raue F, Frank-Raue K, Robinson B, Rosenthal MS, Santoro M, Schlumberger M, Shah M, Waguespack SG. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. (2015) 25(6):567-610.

7. Medical Services Commission. Diabetes care. Victoria (BC) British Columbia Services Commission. Other. (2010) Website: www.guideline.gov/content.aspx?id=38898

8. Diagnosis and management of type 2 diabetes mellitus in adults. Bloomington (MN) Institute for Clinical Systems Improvement (ICSI). Other. (2012) Website: https://www.icsi.org/_asset/3rrm36/Diabetes.pdf