Multiple Endocrine Neoplasia Type IIB

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 03/06/2019
• Curation Status: Released - Under Revision (2.0.1)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
No assertions found.

Actionability Assertion 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.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
No scores were found.

Severity of Outcome

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.

Clinical Features (Signs / symptoms)

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.

Natural History (Important subgroups & survival / recovery)

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.

Likelihood of Outcome

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

Prevalence of Genetic Variants

Unknown

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

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

Without intervention, nearly all (98-100%) patients with MEN2B will develop MTC; about 50% of patients develop PHEO. PHPT is rare (<1%).

Tier 3

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

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

Intervention Effectiveness

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

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

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

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

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

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

Circumstances to Avoid

All glucagon-like peptide 1 (GLP-1) receptor agonists except twice-daily exenatide are contraindicated in patients with MEN2B.

Tier 2

Nature of 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.

Context: Pediatric

Chance to Escape Clinical Detection

50-75% of MEN2B cases are associated with a de novo pathogenic variant.

Context: Pediatric

Tier 4

Most patients with MEN2B are diagnosed when the MTC is clinically evident and too advanced to be cured.

Context: Pediatric

Tier 3

Individuals with undiagnosed PHEO may die from a cardiovascular hypertensive crisis perioperatively.

Context: Pediatric

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers

References List

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