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 1.0.1
• GENE/GENE PANEL: RET
• Condition: Multiple Endocrine Neoplasia IIA, Familial Medullary Thyroid Cancer
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• RET ⇔ 171400: Assertion Pending
• RET ⇔ 155240: 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
Medullary thyroid cancer / Thyroidectomy	2	3C	3A	1	9CA
Pheochromocytoma / Biochemical screening	2	3C	3B	3	11CB
Hyperparathyroidism / Biochemical screening	1	2C	3B	3	9CB

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. Within MEN2, MEN2A accounts for roughly 70-80% of cases, and FMTC accounts for roughly 10-20% of cases. Overall, MEN2A has an estimated prevalence of 1/40,000, while the prevalence of FMTC is unknown. [1, 2, 3, 4, 5]

Clinical Features

MEN2A is associated with an increased risk for medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), and primary hyperparathyroidism (PHPT). Some patients with MEN2A also develop cutaneous lichen amyloidosis (CLA) and disturbances in gut transit that resemble those seen in Hirschprung disease.
FMTC is considered to be a clinical subtype of MEN2A with the presentation of MTC in the absence of PHEO and PHPT due to decreased penetrance. Criteria for FMTC versus MEN2A are not standardized, but include the diagnosis of MTC only in multiple family members either across generations or within a generation. It can be clinically very difficult to determine that a family has FMTC rather than MEN2A since the former diagnosis depends upon the absecnce of PHEO and PHPT. Thus limited family history and young patient age make distinguishing between MEN2A and FMTC difficult. [1, 2, 3, 4, 6]

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 FMTC, MTC typically occurs in middle age. Onset of MEN2A is typically prior to age 35, usually between ages 5 and 25. MTC is generally the first manifestation in MEN2A with probands presenting with a neck mass or neck pain. All individuals with MEN2A who have not had a thyroidectomy will demonstrate biochemical evidence of MTC by age 35. PHEOs usually present after MTC or concomitantly, but are the first manifestation in 13-27% of individuals. PHEOs are diagnosed at an earlier age, have subtler symptoms, and are more likely to be bilateral than sporadic tumors, with malignant transformation occurring in about 4% of cases. PHPT is typically mild, with most individuals with PHPT having no symptoms, and may range from a single adenoma to marked hyperplasia. PHPT usually presents many years after the diagnosis of MTC, with an average age of onset of 38 years. [1, 2, 3, 4, 6]

2. How effective are interventions for preventing harm?

Patient Management

All patients with MEN2 or FMTC should undergo prophylactic thyroidectomy. The recommended timing of surgery is based on a classification system of RET mutations and other indicators of risk for aggressive MTC. RET mutations associated with MEN2A span the categories of "high risk" (thyroidectomy recommended by age 5 or earlier based on calcitonin levels) and "moderate risk" (thyroidectomy considered after age 5 or later based on calcitonin levels). RET mutations associated with FMTC are classified as "moderate risk". The goal of early prophylactic thyroidectomy is to intervene before metastasis, which is associated with a low cure rate. 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, 7]

Surveillance

In MEN2A "moderate risk" cases and FMTC cases where prophylactic thyroidectomy has been delayed, patients should undergo annual basal serum calcitonin testing and cervical neck ultrasound starting at age 5. (Tier 1) [2, 7]

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 MEN2A "high risk" cases and age 16 for MEN2A "moderate risk" and FMTC cases. Surveillance is recommended for FMTC cases because of the inherent uncertainty in definitively assigning this diagnosis. (Tier 2) [2, 7]

Because of the high risk to the fetus and mother, the presence of a PHEO must be excluded in women with a RET mutation associated with MEN2 who are planning a pregnancy or are pregnant. (Tier 2) [2, 7]

Surveillance for PHPT should happen at the same time as surveillance for PHEO and should include include annual albumin-corrected calcium or ionized serum calcium measurements (with or without serum intact-parathyroid hormone [PTH]) beginning at age 11 for MEN2A "high risk" cases and at age 16 years for MEN2A "moderate risk" and FMTC cases. Age to start surveillance is based on the typical age of onset for PHPT. (Tier 2) [2, 7]

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) [8, 9]

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

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

RET mutations are identified in at least 98% cases of MEN2A and in at least 95% of families with FMTC. (Tier 3) [4]

Given MEN2A has an estimated prevalence of 1/40,000, RET mutations that lead to MEN2A are likely to have a similar prevalence. However, the estimated prevalence of FMTC is uknown and information on the frequency of RET mutations associated with FMTC was not available.

Penetrance

For MEN2A, the frequencies of associated outcomes are: 90-98% MTC, 50-57% PHEO, 15-30% PHPT, and 10-15% CLA.
In FMTC, the frequency estimates for MTC range from 80% to 95%. (Tier 3) [4, 2, 3, 5]

Relative Risk

Information regarding relative risk was not available.

Expressivity

Patients carrying the same mutation may show a heterogenic 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 MEN2A and FMTC is typically more aggressive and presents at an earlier age than sporadic MTC and would be highly likely to escape clinical detection in the setting of recommended clinical care. (Tier 3) [4]

Date of Search: 06.04.2015

Reference List

1. Multiple endocrine neoplasia type 2A. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=247698

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. 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

5. Raue F, Rondot S, Schulze E, Szpak-Ulczok S, Jarzab B, Frank-Raue K. Clinical utility gene card for: multiple endocrine neoplasia type 2. Eur J Hum Genet. (2012) 20(1).

6. 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.

7. 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.

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

9. 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