Multiple Endocrine Neoplasia Type 2

Clinical characteristics.

Multiple endocrine neoplasia type 2 (MEN 2) includes the following phenotypes: MEN 2A, FMTC (familial medullary thyroid carcinoma, which may be a variant of MEN 2A), and MEN 2B. All three phenotypes involve high risk for development of medullary carcinoma of the thyroid (MTC); MEN 2A and MEN 2B involve an increased risk for pheochromocytoma; MEN 2A involves an increased risk for parathyroid adenoma or hyperplasia. Additional features in MEN 2B include mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and a marfanoid habitus. MTC typically occurs in early childhood in MEN 2B, early adulthood in MEN 2A, and middle age in FMTC.

Diagnosis/testing.

The diagnosis of MEN 2 is established in a proband who fulfills existing clinical diagnostic criteria. Molecular genetic testing to identify a heterozygous germline RET pathogenic variant is indicated in all individuals with a diagnosis of primary C-cell hyperplasia or MTC or a clinical diagnosis of MEN 2. Identification of a heterozygous germline RET pathogenic variant on molecular genetic testing establishes the diagnosis if clinical features are inconclusive.

Management.

Treatment of manifestations: Treatment for MTC is surgical removal of the thyroid gland and lymph node dissection. External beam radiation therapy or intensity-modulated radiation therapy can be considered for advanced locoregional disease. Kinase inhibitors may be used in metastatic MTC. Pheochromocytomas detected by biochemical testing and radionuclide imaging are removed by adrenalectomy. Primary hyperparathyroidism is treated with surgery to remove one or more parathyroid glands, or more rarely, with medications to reduce parathyroid hormone secretion.

Prevention of primary manifestations: Prophylactic thyroidectomy for individuals with an identified germline RET pathogenic variant.

Prevention of secondary complications: Prior to any surgery in an individual with MEN 2A or MEN 2B, the presence of a functioning pheochromocytoma should be excluded by appropriate biochemical screening.

Surveillance: Annual measurement of serum calcitonin concentration to detect residual or recurrent MTC after thyroidectomy, even if thyroidectomy was performed prior to biochemical evidence of disease. Monitoring for possible hypoparathyroidism in all those who have undergone thyroidectomy and parathyroid autotransplantation. Annual biochemical screening for those with a germline RET pathogenic variant whose initial screening results are negative for pheochromocytoma.

Agents/circumstances to avoid: Dopamine D₂ receptor antagonists and β-adrenergic receptor antagonists present a high risk for adverse reactions in individuals with pheochromocytoma.

Evaluation of relatives at risk: RET molecular genetic testing should be offered to all at-risk members of kindreds in which a germline RET pathogenic variant has been identified.

Pregnancy management: Women with MEN 2 should be screened for pheochromocytoma prior to a planned pregnancy or as early as possible during an unplanned pregnancy.

Genetic counseling.

All MEN 2 phenotypes are inherited in an autosomal dominant manner. The probability of a de novo pathogenic variant is 5% or less in index cases with MEN 2A and 50% in index cases with MEN 2B. Offspring of affected individuals have a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the RET pathogenic variant has been identified in an affected family member.

Suggestive Findings

Multiple endocrine neoplasia type 2 (MEN 2) includes the phenotypes MEN 2A; familial medullary thyroid carcinoma (FMTC), which may itself be a variant of MEN 2A; and MEN 2B.

MEN 2A should be suspected in individuals with one or more specific endocrine tumors: 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.

MEN 2B should be suspected in individuals with distinctive facies including lip mucosal neuromas resulting in thick vermilion of the upper and lower lip, mucosal neuromas of the lips and tongue, medullated corneal nerve fibers, marfanoid habitus, and MTC.

Establishing the Diagnosis

The diagnosis of MEN 2 is established in a proband with the following clinical criteria. Identification of a heterozygous germline RET pathogenic variant by molecular genetic testing (see Table 1) establishes the diagnosis if clinical features are inconclusive.

Clinical criteria, as outlined by Kloos et al [2009]:

• MEN 2A is diagnosed clinically by the occurrence of two or more specific endocrine tumors (medullary thyroid carcinoma [MTC], pheochromocytoma, or parathyroid adenoma/hyperplasia) in a single individual or in close relatives.
• FMTC is diagnosed in families with four or more cases of MTC in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia.
• MEN 2B is diagnosed clinically by the presence of early-onset MTC, mucosal neuromas of the lips and tongue, as well as medullated corneal nerve fibers, distinctive facies with enlarged lips, and an asthenic, marfanoid body habitus.

When the phenotypic and laboratory findings suggest the diagnosis of MEN 2, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

Single-gene testing. Sequence analysis of RET detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.

• Select-exon testing. The majority of pathogenic variants occur in exons 10, 11, and 13-16 (Table 3). Sequence analysis of select exons and targeted analysis for pathogenic variants may be offered by some laboratories.
  If no pathogenic variant is found by select-exon testing, full-gene sequencing of RET as part of a multigene panel should be considered next.
  Note: Since MEN 2 occurs through a gain-of-function mechanism and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplications is not indicated.

A cancer predisposition multigene panel that includes RET and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

The endocrine disorders observed in multiple endocrine neoplasia type 2 (MEN 2) are: medullary thyroid carcinoma (MTC) and/or its precursor, C-cell hyperplasia (CCH); pheochromocytoma; and parathyroid adenoma or hyperplasia.

Genotype-Phenotype Correlations

Pathogenic variants involving the cysteine codons 609, 618, and 620 in exon 10 of RET are associated with MEN 2A, FMTC, and HSCR1 [Mulligan et al 1994, Decker et al 1998, Romeo et al 1998, Inoue et al 1999, Takahashi et al 1999]. A pathogenic variant in one of these codons is detected in about 10% of families with MEN 2A and more than 50% of families with FMTC; these pathogenic variants are associated with low transforming activity of RET [Takahashi et al 1998, Hansford & Mulligan 2000].

RET germline pathogenic variant p.Met918Thr is only associated with MEN 2B; however, somatic pathogenic variants at this codon are frequently observed in MTC in individuals with no known family history of MTC, and are overrepresented in individuals with sporadic MTC who have the RET germline variant p.Ser836 [Gimm et al 1999].

Any RET pathogenic variant at codon 634 in exon 11 results in a higher incidence of pheochromocytomas and hyperparathyroidism [Eng et al 1996, Yip et al 2003, Zbuk & Eng 2007, Kloos et al 2009].

• A report of 12 Brazilian families indicated that p.Cys634Arg is associated with a higher probability of having metastases at diagnosis than other codon 634 pathogenic variants [Puñales et al 2003].
• Codon 634 pathogenic variants are also associated with development of cutaneous lichen amyloidosis [Seri et al 1997]. Among 25 individuals from three families with a codon 634 pathogenic variant, 36% had cutaneous lichen amyloidosis [Verga et al 2003].
• While 25% of FMTC kindreds harbor a pathogenic variant in codon 634, p.Cys634Arg pathogenic variants are virtually absent in this subtype [Hansford & Mulligan 2000, Zbuk & Eng 2007].

Pathogenic variants at codons 768, 804, and 891 that were initially only associated with MTC have subsequently been found in families with MEN 2A [Jimenez et al 2004a, Aiello et al 2005, Schulte et al 2010].

• Initially thought to be associated with MTC only, pathogenic variants at codon 804 in exon 14 (e.g., p.Val804Leu and p.Val804Met) were subsequently identified in individuals with pheochromocytoma [Nilsson et al 1999, Høie et al 2000, Gibelin et al 2004, Jimenez et al 2004a].
• Disease expression of pathogenic variants at codon 804 has been shown to be highly variable, even within the same family [Feldman et al 2000, Frohnauer & Decker 2000]. Some individuals with such pathogenic variants have had MTC at age five years and fatal metastatic MTC at age 12 years, whereas other individuals with the same pathogenic variant have been shown to have normal thyroid histology at age 27 years, normal biochemical screening at age 40 years, and no clinical evidence of MTC at age 86 years.
• In another large family with a high level of consanguinity, biochemical testing indicated expression of thyroid disease in individuals homozygous but not heterozygous for p.Val804Met [Lecube et al 2002].
• Cutaneous lichen amyloidosis in association with a p.Val804Met pathogenic variant has been reported in one individual [Rothberg et al 2009].

One study suggests that in addition to their association with MTC, pathogenic variants in codons 790 or 804 may be associated with papillary thyroid carcinoma [Brauckhoff et al 2002]. In a large Italian family, 40% of family members with a p.Val804Met pathogenic variant who were examined in detail had concomitant medullary and papillary thyroid carcinoma [Shifrin et al 2009].

The American Thyroid Association Guidelines Task Force has classified pathogenic variants based on their risk for aggressive MTC [Kloos et al 2009]. The classification may be used in (1) predicting phenotype and in (2) recommendations regarding the ages at which to (a) perform prophylactic thyroidectomy and (b) begin biochemical screening for pheochromocytoma and hyperparathyroidism (see Table 3 and Surveillance).

Penetrance

The penetrance for MTC, pheochromocytoma, and parathyroid disease varies by MEN 2 phenotype (see Table 2).

Nomenclature

MEN 2A is also referred to as Sipple syndrome.

Mucosal neuroma syndrome is a synonym for MEN 2B. MEN 2B was initially called Wagenmann-Froboese syndrome [Morrison & Nevin 1996].

Prevalence

The prevalence of MEN 2 has been estimated at 1:35,000 [DeLellis et al 2004].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with multiple endocrine neoplasia type 2 (MEN 2), the following evaluations are recommended if they have not already been completed:

• Referral to an endocrinologist
• Consultation with a clinical geneticist and/or genetic counselor
• Biochemical evaluations:
  • Plasma calcitonin
  • Plasma catecholamines and metanephrines
  • Serum calcium and parathyroid hormone
• Evaluation for metastatic disease in individuals with MTC
  • CT with contrast for chest and abdomen
  • MRI of liver in the presence of nodal disease or calcitonin >400 pg/mL

Treatment of Manifestations

Medullary thyroid carcinoma (MTC). Standard treatment for MTC is surgical removal of the thyroid and lymph node dissection [Kloos et al 2009, National Comprehensive Cancer Network 2015]. Current NCCN guidelines recommend consideration of therapeutic external beam radiation therapy or intensity-modulated radiation therapy for incomplete tumor resection or extrathyroidal extension with positive margins [National Comprehensive Cancer Network 2015]. Several kinase inhibitors – vandetanib, cabozantinib, and BLU-667 – have improved progression-free survival and in some cases cause disease regression in unresectable or advanced metastatic MTC [Elisei et al 2013, Wells et al 2013, Subbiah et al 2018].

All individuals who have undergone thyroidectomy need thyroid hormone replacement therapy.

Autotransplantation of parathyroid tissue is not typically performed at the time of thyroidectomy unless there is evidence of hyperparathyroidism [Kloos et al 2009].

Pheochromocytomas detected by biochemical testing and radionuclide imaging are removed by adrenalectomy, which may be performed using video-assisted laparoscopy. Historically, some specialists recommended bilateral adrenalectomy at the time of demonstration of tumor on just a single adrenal gland because of the strong probability that the other adrenal gland would develop a tumor within ten years. However, because of the risk for adrenal insufficiency and Addisonian crisis following bilateral adrenalectomy, most experts now recommend unilateral adrenalectomy in unilateral tumors and cortical-sparing adrenal surgery with close monitoring of the remnant tissue in persons with one remaining adrenal gland or bilateral pheochromocytoma [Kloos et al 2009, Neumann et al 2019].

Hypertensive treatment prior to adrenalectomy often involves the use of α- and β-adrenergic receptor blockade [Pacak et al 2005], although some centers do not pretreat with α-blockade and use nitroprusside to control blood pressure during surgery [Neumann et al 2019].

Parathyroid adenoma or hyperplasia diagnosed at the time of thyroidectomy is treated either with resection of the visibly enlarged parathyroid gland(s), subtotal parathyroidectomy, or total parathyroidectomy with forearm autograft [Kloos et al 2009]. However, in most individuals with MEN 2A, hyperparathyroidism is diagnosed many years after thyroidectomy.

Individuals with biochemical evidence of primary hyperparathyroidism who have undergone prior thyroidectomy should have preoperative localization with excision of the localized hypertrophied parathyroid glands and forearm autotransplantation.

Therapy with medications to control primary hyperparathyroidism should be considered in individuals with a high risk for surgical mortality, limited life expectancy, or persistent or recurrent primary hyperparathyroidism after one or more surgical attempts [Kloos et al 2009].

Prevention of Primary Manifestations

Prophylactic thyroidectomy is the primary preventive measure for individuals with an identified germline RET pathogenic variant [Cohen & Moley 2003, Kloos et al 2009].

Prophylactic thyroidectomy is safe for all age groups; however, the timing of the surgery is controversial [Moley et al 1998]. According to the American Thyroid Association Guidelines Task Force consensus statement, the age at which prophylactic thyroidectomy is performed can be guided by the codon position of the RET pathogenic variant (see Table 3 and Genotype-Phenotype Correlations) [Kloos et al 2009]. However, these guidelines continue to be modified as more data become available.