Clinical Guidance

p.Cys609, p.Cys611, p.Cys618, and p.Cys620. Pathogenic variants involving the cysteine codons 609, 611, 618, and 620 in exon 10 of RET are associated with MEN2A, FMTC, and Hirschsprung disease [, , , , ]. A pathogenic variant in one of these codons is detected in about 10% of families with MEN2A and more than 50% of families with FMTC; these pathogenic variants are associated with low transforming activity of RET . p.Cys634. Any RET pathogenic variant at codon 634 in exon 11 results in a higher incidence of pheochromocytomas and HPT [, , , ].

Source: GeneReviews — "Multiple Endocrine Neoplasia Type 2"

Penetrance

Penetrance of some RET pathogenic variants is incomplete, as the incidence of MTC, pheochromocytoma, and parathyroid disease varies by MEN2 phenotype .

Source: GeneReviews — "Multiple Endocrine Neoplasia Type 2"

Diagnostic Criteria

Clinical diagnostic criteria for multiple endocrine neoplasia type 2 (MEN2) have been published ; see .

Suggestive Findings

MEN2 includes the phenotypes MEN2A; familial medullary thyroid carcinoma (FMTC), which may itself be a variant of MEN2A; and MEN2B. MEN2A should be suspected in individuals with one or more specific endocrine tumor(s): medullary thyroid carcinoma (MTC), pheochromocytoma, or parathyroid adenoma/hyperplasia. FMTC should be suspected in families with more than one individual diagnosed with MTC in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia.

Source: GeneReviews — "Multiple Endocrine Neoplasia Type 2"

Differential Diagnosis

Medullary thyroid carcinoma (MTC) accounts for approximately 10% of new thyroid cancer diagnoses in the United States. Sporadic MTC (i.e., the chance occurrence of MTC in a single family member that is not expected to recur in other family members) tends to be unifocal, have a later age of onset, and lack C-cell hyperplasia (CCH) . A somatic RET pathogenic variant, in the absence of a RET germline pathogenic variant, is identified in 40%-50% of MTCs [, , , ]. The somatic variant is the most common; variants at other codons as well as small in-frame deletions have been reported . Tumors with a somatic codon 918 variant appear to be more aggressive . C-cell hyperplasia (CCH). CCH associated with a positive calcitonin stimulation test occurs in about 5% of the general population. Serum calcitonin levels may be elevated in persons with chronic kidney failure, sepsis, neuroendocrine tumors of the lung or gastrointestinal tract, hypergastrinemia, mastocytosis, autoimmune thyroid disease, and type 1A pseudohypoparathyroidism . Secondary CCH has been described occasionally in the setting of aging and hyperparathyroidism (HPT). Secondary CCH rarely transforms to MTC and is not related to MEN2. Pheochromocytoma. Up to 25% of individuals with pheochromocytoma and no known family history of pheochromocytoma have a heterozygous germline pathogenic variant in one of several genes: RET, VHL, SDHD, or SDHB . Approximately 5% of individuals with nonsyndromic pheochromocytoma and no family history of pheochromocytoma were heterozygous for a germline RET pathogenic variant . See for genes associated with susceptibility for pheochromocytoma. Evaluation of biochemical features can help differentiate MEN2-associated pheochromocytoma. compared biochemical profiles for inherited and sporadic pheochromocytoma and found that MEN2 can be ruled out in pheochromocytomas that exclusively produce normetanephrine. Table 4. Pheochromocytoma Susceptibility Genes in the Differential Diagnosis of Multiple Endocrine Neoplasia Type 2

Management Guidelines

Clinical practice guidelines for multiple endocrine neoplasia type 2 (MEN2) have been published . Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with MEN2, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 5. Multiple Endocrine Neoplasia Type 2: Recommended Evaluations Following Initial Diagnosis

Source: GeneReviews — "Multiple Endocrine Neoplasia Type 2"

Clinical Guidance

Dopamine D2 receptor antagonists (e.g., metoclopramide and veralipride) and beta-adrenergic receptor antagonists (-blockers) have a high potential to cause an adverse reaction in individuals with pheochromocytoma. Other medications including monoamine oxidase inhibitors, sympathomimetics (e.g., ephedrine), and certain peptide and corticosteroid hormones may also cause complications; tricyclic antidepressants are inconsistent in causing adverse reactions .

Source: GeneReviews — "Multiple Endocrine Neoplasia Type 2"

Therapies Under Investigation

Clinical trials of multikinase inhibitors such as sorafenib, sunitinib, and regorafenib are currently under way. National Comprehensive Cancer Network and American Thyroid Association guidelines recommend consideration of clinical trial participation for individuals who fail standard treatment with a tyrosine kinase inhibitor such as vandetanib or cabozantinib . Newer RET-selective inhibitors including selpercatinib (LOXO-292) pralsetinib (BLU-667) are now approved as second-line treatment for metastatic MTC after failure of first-line multikinase inhibitors . Sorafenib is FDA approved for use in renal cell and hepatocellular carcinoma.

Source: GeneReviews — "Multiple Endocrine Neoplasia Type 2"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended .

Table 8.

Multiple Endocrine Neoplasia Type 2: Recommended Surveillance

System/Concern | Evaluation | Frequency

MTC | Serum calcitonin | In those who have not had prophylactic thyroidectomy:

• MEN2A/FMTC: annually beginning at age 3-5 yrs

• MEN2B: annually beginning at age 6 mos1

In persons after thyroidectomy: 3 mos postoperatively, followed by annually; more frequently in those w/residual MTC2

Plasma CEA | In persons after thyroidectomy: 3 mos postoperatively, followed by annually; more frequently in those w/residual MTC2

PCC | Plasma free metanephrines or 24-hour urine for fractionated metanephrines | In all persons prior to any surgery

• Plasma free metanephrines or 24-hour urine for fractionated metanephrines

• MRI /or CT if biochemical results are abnormal

| • MEN2A/FMTC: annually beginning at age 11 yrs in persons w/ATA H RET pathogenic variant; annually beginning at age 16 yrs in persons w/ATA MOD RET pathogenic variant

• MEN2B: annually beginning at age 11 yrs

• Women: prior to a planned pregnancy, or as early as possible during an unplanned pregnancy

Other screening studies, such as scintigraphy or positron emission tomography | As needed

Parathyroid adenoma or hyperplasia

| Albumin-corrected calcium or ionized calcium | In those who have not had parathyroidectomy parathyroid autotransplantation:

Source: GeneReviews — "Multiple Endocrine Neoplasia Type 2"