Pediatric Summary Report

Secondary Findings in Pediatric Subjects

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

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released - Under Revision 1.1.3
• Status (Adult): Incomplete (Consensus scoring is Incomplete)
• GENE/GENE PANEL: RET
• Condition: Multiple Endocrine Neoplasia Type IIB
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• RET ⇔ 0008082 (multiple endocrine neoplasia type 2b): Strong Actionability

Actionability Rationale

The assertion is traditionally done on the highest scoring outcome-intervention pair, which in this case is pheochromocytoma / biochemical surveillance. However, the committee reflected that the reason for a strong assertion is the much more compelling evidence for prevention of medullary thyroid cancer by prophylactic thyroidectomy, which scores lower, but it is because of the nature of the intervention, which is a thyroidectomy. The scorers acknowledge that there is evidence of a genotype and phenotype correlation with respect to medullary thyroid carcinoma. Recognizing that thyroidectomy is an invasive procedure, which lowers the score, the effectiveness of the intervention leads to a strong assertion.

Final Consensus Scores

Gene Condition Pairs: RET ⇔ 0008082 (OMIM:162300)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Medullary thyroid carcinoma / Prophylactic thyroidectomy	2	3C	3B	1	9CB
Pheochromocytoma / Biochemical Surveillance	2	3C	3D	3	11CD

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 2 (MEN2) has two main subtypes, MEN2A and MEN2B. The exact prevalence of MEN2B is unknown but it accounts for 5 to 10% of all cases of MEN2, providing an estimated prevalence of 1/700,000 to 1/350,000. This report includes MEN2B; MEN2A is covered separately. [1, 2, 3, 4]

Clinical Features

MEN2B is a rare, aggressive form of MEN2. characterized by medullary thyroid carcinoma (MTC) with or without pheochromocytoma (PHEO). In contrast to MEN2A, MEN2B is not associated with an increased risk for hyperparathyroidism. MEN2B is associated with developmental features including mucosal neuromas of the lips, eyelids, and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, ophthalmological abnormalities (e.g., inability to make tears in infancy and medullated corneal nerve fibers), and marfanoid body habitus (with joint laxity and skeletal abnormalities). Chronic constipation, abdominal distension, diarrhea, or megacolon at birth can be the initial manifestations of the disease due to ganglioneuromatosis of the gastrointestinal tract, and some patients require surgery for bowel obstruction. Patients with PHEOs can have associated symptoms of headache, palpitations, nervousness, hypertension and tachycardia. Though possible, primary hyperparathyroidism (PHPT) is rare. [1, 2, 3, 4, 5, 6, 7, 8, 9]

Natural History

MTC is usually the first manifestation of disease in individuals with MEN2. 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 patients with MEN2B, the MTC presents in infancy or early childhood and is highly aggressive, metastasizing early to regional lymph nodes and beyond. A rare group of patients have atypical MEN2B that develops around 20 to 30 years of age; these patients have dual tandem RET pathogenic variants. Individuals with MEN2B who do not undergo thyroidectomy prior to age 1 will develop metastatic MTC at an early age; even distant metastases can develop within the first year. Without thyroidectomy, the average age of death for those with MEN2B is age 21. PHEOs occur in only 50% of individuals and may develop as early as 12 years of age; 50% of those are multiple and often bilateral. Even without malignant progression, PHEOs can be lethal from intractable hypertension or anesthesia-induced hypertensive-crises. MEN2B individuals may be identified in infancy or early childhood by the presence of mucosal neuromas, a distinctive facial appearance, and lack of tear production. [1, 2, 3, 4, 5, 6, 7, 8, 9]

2. How effective are interventions for preventing harm?

Patient Management

Upon diagnosis, initial evaluation should include physical exam and ultrasound of the neck, basal carcinoembryonic antigen (CEA) and calcitonin levels, and PHEO screening. (Tier 2) [5, 6, 7, 8]

Additionally, the following evaluations are recommended at diagnosis: Referral to an endocrinologist, consultation with a clinical geneticist and/or genetic counselor, plasma catecholamines and metanephrines, serum calcium and parathyroid hormone, and workup to evaluate for metastases when MTC is present. (Tier 4) [4]

Experienced physicians and surgeons with experience in pediatric thyroid surgery in tertiary care centers should be responsible for the management of children with MEN2B, especially in view of the risks of thyroidectomy in very young children. (Tier 2) [5, 8]

The cornerstone of MTC management for patients with MEN2B is prophylactic thyroidectomy within the first six-months to year of life due to the early development of MTC and metastases in these children. The exact timing depends on surgical expert recommendations and taking into consideration preferences of the patient’s parents. Preserving the parathyroid glands should be a priority and should guide extent of central neck dissection. In a study of 44 children with MEN2B, three patients had a thyroidectomy during the first year of life and were cured. Further, all nine children having thyroidectomy prior to age 4 years were cured biochemically, compared to only 1 of 35 children having thyroidectomy after age 5 years. (Tier 2) [5, 6, 7, 8, 10, 11]

Biochemical screening for PHEO should be performed prior to any planned surgery or pregnancy regardless of age. PHEOs should be removed prior to thyroidectomy. Preoperative alpha-adrenergic blockade is essential for patients with catecholamine-secreting PHEOs to mitigate risk of intraoperative hypertensive crisis. Undiagnosed PHEO can result in substantial morbidity and even death as a result of hypertensive crisis during surgery. (Tier 2) [5, 6, 7, 8]

Surveillance

Biochemical screening for PHEO should begin at age 11 for patients with MEN2B. Older guidelines have suggested PHEO surveillance should begin as early at the time of thyroidectomy or by 5-8 years of age. (Tier 2) [5, 6, 8, 10]

Circumstances to Avoid

All glucagon-like peptide 1 (GLP-1) receptor agonists except twice-daily exenatide are contraindicated in patients with MEN2B. (Tier 2) [12, 13]

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

Mode of Inheritance

Autosomal Dominant
A rare group of patients have atypical MEN2B that develops around 20 to 30 years of age; these patients have dual tandem RET pathogenic variants. [1, 2, 3, 4, 5, 6, 7, 8, 9]

Prevalence of Genetic Variants

RET pathogenic variants are identified in more than 98% of MEN2B cases.
Information on the population frequency of RET pathogenic variants associated with MEN2B was not available. (Tier 3) [4, 7]

Penetrance

Without intervention, nearly all (98-100%) patients with MEN2B will develop MTC; about 50% of patients develop PHEO. PHPT is rare (<1%). (Tier 3) [4, 5, 6, 7, 8]

Relative Risk

Information regarding relative risk was not available.

Expressivity

Patients carrying the same pathogenic variant may show a heterogeneous progression of disease. Even within the same family, the natural course of disease may vary. (Tier 4) [2, 6]

4. What is the Nature of the Intervention?

Nature of Intervention

Compared to adults, children, and especially infants, have higher complication rates associated with thyroidectomy and node dissection, the most significant being hypoparathyroidism. There is some concern about potential detrimental effects of insufficient thyroid hormone replacement in young children, such as impaired brain development and slowed growth. The surveillance interventions identified herein are biochemical monitoring and imaging by ultrasound. Patients who have had adrenalectomy secondary to PHEO are at risk of adrenal crisis, which can cause death, during stressors and may require corticosteroid replacement therapy for adrenal insufficiency, depending on extent of resection. Following adrenalectomy, alpha blockade is necessary to treat hypotension. All patients undergoing thyroidectomy require thyroid hormone replacement therapy, and patients at risk for hypoparathyroidism must be monitored. Additionally, following thyroidectomy, patients must continue to be surveilled: calcitonin and CEA levels every six months for one year and then annually. [1, 4, 5, 6, 7, 8, 10]

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

Chance to Escape Clinical Detection

50-75% of MEN2B cases are associated with a de novo pathogenic variant. (Tier 4) [4, 5]

Most patients with MEN2B are diagnosed when the MTC is clinically evident and too advanced to be cured. (Tier 3) [5]

Individuals with undiagnosed PHEO may die from a cardiovascular hypertensive crisis perioperatively. (Tier 4) [4]

Date of Search: 06.04.2015 (updated 03.06.2019)

Reference List

1. Multiple endocrine neoplasia. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=276161

2. Multiple endocrine neoplasia type 2. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=653

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

4. J Marquard, C Eng. Multiple Endocrine Neoplasia Type 2. 1999 Sep 27 [Updated 2015 Jun 25]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1257

5. 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.

6. Wasserman JD, Tomlinson GE, Druker H, Kamihara J, Kohlmann WK, Kratz CP, Nathanson KL, Pajtler KW, Parareda A, Rednam SP, States LJ, Villani A, Walsh MF, Zelley K, Schiffman JD. Multiple Endocrine Neoplasia and Hyperparathyroid-Jaw Tumor Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood. Clin Cancer Res. (2017) 23(13):e123-e132.

7. National Comprehensive Cancer Network. Neuroendocrine and Adrenal Tumors: NCCN Evidence Blocks Version 1.2019. (2019) Accessed: 2019-03-06. Website: https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine_blocks.pdf

8. National Comprehensive Cancer Network. Thyroid Carcinoma: NCCN Evidence Blocks Version 3.2018. (2018) Accessed: 2019-03-06. Website: https://www.nccn.org/professionals/physician_gls/pdf/thyroid_blocks.pdf

9. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIB; MEN2B. MIM: 162300: 2016 Oct 13. World Wide Web URL: http://omim.org.

10. 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.

11. Cocks HC. A review of the evidence base for the management of thyroid disease. A summary of the proceedings of the 8th annual evidence-based medicine day, Freeman Hospital, Newcastle, 4 November 2004. Clin Otolaryngol. (2005) 30(6):500-10.

12. Handelsman Y, Bloomgarden ZT, Grunberger G, Umpierrez G, Zimmerman RS, Bailey TS, Blonde L, Bray GA, Cohen AJ, Dagogo-Jack S, Davidson JA, Einhorn D, Ganda OP, Garber AJ, Garvey WT, Henry RR, Hirsch IB, Horton ES, Hurley DL, Jellinger PS, Jovanovic L, Lebovitz HE, LeRoith D, Levy P, McGill JB, Mechanick JI, Mestman JH, Moghissi ES, Orzeck EA, Pessah-Pollack R, Rosenblit PD, Vinik AI, Wyne K, Zangeneh F. American association of clinical endocrinologists and american college of endocrinology - clinical practice guidelines for developing a diabetes mellitus comprehensive care plan - 2015. Endocr Pract. (2015) 21 Suppl 1:1-87.

13. BCGuidelines.ca. Diabetes Care. (2015) Accessed: 2019-01-15. Website: https://www2.gov.bc.ca/assets/gov/health/practitioner-pro/bc-guidelines/diabetes_care_full_guideline.pdf