Multiple Endocrine Neoplasia IIA, Familial Medullary Thyroid Cancer

Actionability Adult Summary Report

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

• Gene: RET (HGNC:9967)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 03/06/2019
• Curation Status: Released - Under Revision (2.0.2)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
RET	familial medullary thyroid carcinoma (0007958)	155240	Strong Actionability
RET	multiple endocrine neoplasia type 2A (0008234)	171400	Strong Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion computed according to the rubric. 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 the effectiveness of prophylactic thyroidectomy for medullary thyroid cancer prevention.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Medullary thyroid cancer / Prophylactic Thyroidectomy	2	3C	3A	1	9CA
Pheochromocytoma / Biochemical surveillance	2	3C	3D	3	11CD
Hyperparathyroidism / Biochemical surveillance	1	2C	3D	3	9CD

Severity of Outcome

Prevalence of the Genetic Condition

Multiple endocrine neoplasia type 2 (MEN2) has two main subtypes, MEN2A and MEN2B, with familial medullary thyroid carcinoma (FMTC) being a clinical subtype within the MEN2A spectrum. Within MEN2, MEN2A accounts for roughly 70-80% of MEN2 cases, and FMTC accounts for roughly 5-20% of MEN2 cases. Overall, MEN2A has an estimated prevalence of 1/40,000, while the prevalence of the FMTC subtype of MEN2A is unknown. This report includes MEN2A and the clinical subtype of MEN2A FMTC.; MEN2B is covered separately and assessed in the pediatric context only.

Clinical Features (Signs / symptoms)

MEN2A is a hereditary cancer syndrome characterized by medullary thyroid carcinoma (MTC) in combination with pheochromocytoma (PHEO), parathyroid adenoma, and/or primary mild hyperparathyroidism (PHPT). Renal malformations have also been reported. Patients with PHEOs can have associated symptoms of headache, palpitations, nervousness, hypertension and tachycardia, and a risk of hypertensive crisis. The PHEOs are almost always benign and are usually multicentric, bilateral, and confined to the adrenal gland. If PHPT is present, it is usually mild but may manifest symptoms such as depression, muscle weakness, and fatigue. A subset of patients also develop primary localized cutaneous lichen amyloidosis (CLA) which causes dermatological lesions and intense pruritis; another subset of patients experiences disturbances in gut transit known as Hirschsprung disease.FMTC is 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 have not been standardized but include the diagnosis of MTC only in multiple family members either across generations or within a generation. Primary localized CLA has also been reported in a family in which multiple affected members met criteria for FMTC rather than MEN2A; likewise, Hirschsprung manifestations and renal malformations have also been reported as comorbid. It can be clinically difficult to determine that a family has FMTC rather than MEN2A since the former diagnosis depends upon the absence of PHEO and PHPT, and there remains the risk to develop PHEO in patients with an uncertain diagnosis.

Natural History (Important subgroups & survival / recovery)

RET pathogenic variants associated with MEN2A span the categories of “high-risk” and “moderate-risk”; RET pathogenic variants associated with FMTC are classified as “moderate risk.” Penetrance of individual manifestations and age of onset vary by risk. 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. 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. Metastatic spread is common. MTC is the most common cause of death in patients with MEN2A. In FMTC, the age of MTC onset is later than in other types of MEN2A (typically occurs in middle age) and the penetrance is lower. PHEOs usually present after MTC or concomitantly but are the first manifestation in 13-27% of individuals; they occur in about 50% 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. Even without malignant progression, PHEOs can be lethal from intractable hypertension or anesthesia-induced hypertensive crises. Depending on the risk category of the RET pathogenic variant, PHEOs have been observed as early as 5 years of age. PHPT is typically mild, with most individuals with PHPT having no symptoms, and may range from a single adenoma to marked hyperplasia. PHPT occurs in about 20-30% of individuals and usually presents many years after the diagnosis of MTC, with an average age of onset of 38 years.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Dual tandem germline pathogenic variants in RET have been identified in patients with the FMTC phenotype.

Prevalence of Genetic Variants

Unknown

RET pathogenic variants are identified in 95-98% cases of MEN2A and in 88-95% of families with FMTC. RET pathogenic variants that lead to MEN2A are likely to have a similar prevalence as that of the disorder. However, the estimated prevalence of FMTC is unknown and information on the frequency of RET pathogenic variants associated with FMTC was not available.

Tier 3

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

>= 40 %

RET pathogenic variants associated with MEN2A span the categories of “high-risk” and “moderate-risk”; RET pathogenic variants associated with FMTC are classified as moderate risk. Penetrance of individual manifestations vary by risk. In classical MEN2A, almost all (90-100%) patients develop MTC but the penetrance of PHEO and PHPT is partially dependent on the RET pathogenic variant. The variant with the highest penetrance for PHEO has a penetrance of 88% by age 77, and the highest penetrance genotype for PHPT is up to 30%; however, penetrance for PHPT in patients with moderate risk variants may be as low as 2% and penetrance for PHEO in moderate risk variants is around 10-50%.

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, serum calcium and parathyroid hormone, 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, 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 MEN2A, especially in view of the risks of thyroidectomy in very young children.

Tier 2

Prophylactic thyroidectomy is the cornerstone of management for MTC for patients with MEN2A, including FMTC. The recommended timing of surgery is based on a classification system of RET pathogenic variants and other indicators of risk for aggressive MTC, as well as patient/parent preference. Penetrance of individual manifestations and age of onset vary by category of risk, and as such, guideline recommendations vary by variant category. In the setting of a “high-risk” variant, thyroidectomy is recommended by age 5 or earlier based on calcitonin levels, or when the pathogenic variant is identified, if identified at an older age. In the setting of a “moderate-risk” variant, thyroidectomy is recommended after age 5 guided by calcitonin levels and patient preference; this evaluation period may extend into adulthood (or begin in adulthood depending on timing of diagnosis). Patients or parents who do not wish to embark on a lengthy evaluation period or who are at risk for nonadherence to surveillance should be encouraged to opt into early thyroidectomy. The goal of early prophylactic thyroidectomy is to intervene before metastasis, which is associated with a low cure rate. Detection and intervention of MTC can significantly alter associated morbidity and mortality. In historical MEN2A series with treatment initiated after the identification of a thyroid nodule, MTC progressed and showed 15–20% mortality, but early thyroidectomy may have lowered the mortality from hereditary MTC to less than 5%; however, these studies are limited by follow-up period (25 years).

Tier 2

A systematic review of MEN2A case series and case reports found that in a total of 260 cases, 42 (16%) underwent early total thyroidectomy (ETT; defined as thyroidectomy between age 1 and 5), and 218 (84%) underwent late total thyroidectomy (LTT; after age 5). During a median follow-up period of 2 years (range: 0–15 years) for 74 patients (28%), 21 of 65 of the LTT group versus 0 of 9 of the ETT group had progressive and recurrent disease.

Tier 1

Prior to thyroidectomy, preoperative workup should include screening for PHPT. During thyroidectomy, enlarged parathyroid glands should be resected if there is biochemical evidence of PHPT; preservation and autotransplant of thyroid tissue may be necessary depending on extent of resection. This manifestation is less common in children, but parathyroid resection is still indicated in that setting. There are little data on long-term outcomes due to the rarity of this manifestation in childhood.

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

For MEN2A children with a “high-risk” pathogenic variant, patients should undergo annual ultrasound and screening for increased calcitonin levels starting at 3 years of age and proceed to thyroidectomy when elevated levels are detected or at 5 years of age. For patients with a “moderate-risk” pathogenic variant, considering the clinical variability of disease expression in family members in this category, annual physical examination, cervical US, and measurement of serum calcitonin levels, should begin at 5 years of age. For adults who have normal calcitonin at diagnosis, annual screening should guide timing of thyroidectomy.

Tier 2

Biochemical surveillance for PHPT should begin at 11 years and 16 years of age for patients with high- and moderate-risk variants, respectively; this screening is recommended annually for “high-risk” patients and at least every 2-3 years in “moderate-risk” patients.

Tier 2

Following thyroidectomy, patients must continue to be surveilled: calcitonin and CEA levels every six months for one year and then annually.

Tier 2

Biochemical screening for PHEO should begin at age 11 for patients with high-risk variants and age 16 for patients with moderate-risk variants. FMTC patients are recommended for surveillance because of the uncertainty of the diagnosis. 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 MEN2A.

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. Additionally, following thyroidectomy, patients must continue to be surveilled: calcitonin and CEA levels every six months for one year and then annually.

Context: Adult Pediatric

Chance to Escape Clinical Detection

In light of the earlier and more aggressive presentation of MTC in MEN2A, it would be likely to escape early clinical detection in the setting of standard care.

Context: Adult Pediatric

Tier 3

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

Context: Adult Pediatric

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			RET			155240	0007958
RET			171400	0008234

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