Gene test interpretation: RET (multiple endocrine neoplasia type 2 gene)

INTRODUCTION — This monograph summarizes the interpretation of germline genetic testing of RET, the gene associated with multiple endocrine neoplasia type 2 (MEN2). Affected individuals are heterozygous for a pathogenic variant in RET. Evaluation and management of MEN are discussed in detail separately [1]. (See 'Information about MEN2' below.)

RET gene — The rearranged during transfection (RET) proto-oncogene is a transmembrane glycoprotein receptor with tyrosine kinase activity that transduces growth and differentiation signals in several developing tissues, including those derived from the neural crest. Pathogenic, germline variants in RET resulting in gain-of-function cause MEN2, whereas somatic RET mutations are associated with sporadic medullary thyroid cancers. RET rearrangements may also occur in other cancers. The majority of pathogenic variants in RET involve one of five cysteine residues in the cysteine-rich region of the RET protein's extracellular domain. These residues are encoded in exons 10 (codons 609, 611, 618, and 620) or 11 (codon 634) in the RET gene (figure 1). Transmission is autosomal dominant; heterozygosity for a pathogenic or likely pathogenic variant in the RET gene is sufficient to cause MEN2. The pathogenic variant in RET is de novo in 5 to 15 percent and 50 percent of patients with MEN2A and MEN2B, respectively [2]. Thus, a negative family history should not be used to exclude the diagnosis. (See "Classification and genetics of multiple endocrine neoplasia type 2", section on 'Molecular genetics'.)

How to read the report — It is essential to confirm that the result applies to the tested individual and determine whether testing was performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (or other nationally certified laboratory); if this is not the case, testing should be repeated in a certified laboratory.

These and other caveats are summarized in the checklist (table 1).

Disease association — MEN2 is characterized by the triad of medullary thyroid cancer (MTC), pheochromocytoma, and primary parathyroid hyperplasia. MEN2 is subclassified into two distinct syndromes: MEN2A (95 percent) and MEN2B (5 percent) (table 2).

The diagnosis is generally suspected on clinical grounds and established by genetic testing that identifies a pathogenic, or likely pathogenic, variant in RET. If a pathogenic RET variant cannot be identified, it may be possible to make the diagnosis clinically, although an estimated 98 percent of patients with MEN2 are found to have a pathogenic variant in RET after genetic testing.

Multiple endocrine neoplasia type 2A — Within MEN2A, there are four clinical subtypes: classical MEN2A, MEN2A with cutaneous lichen amyloidosis (CLA), MEN2A with Hirschsprung disease (HD), and familial medullary thyroid cancer (FMTC).

Classical MEN2A — This is the most common subtype of MEN2A and is associated with a heritable predisposition to MTC, pheochromocytoma, and primary parathyroid hyperplasia. The respective frequency of these tumors in classical MEN2A is over 90 percent for MTC, approximately 10 to 50 percent for pheochromocytoma (which is often bilateral), and 10 to 30 percent for multigland parathyroid hyperplasia. MEN2A is typically associated with pathogenic variants in exon 10 and 11 of RET (figure 1). The frequency of the development of MTC, pheochromocytoma, and parathyroid hyperplasia depends upon the specific variant.

MEN2A with cutaneous lichen amyloidosis — Cutaneous lichen amyloidosis (CLA, also called lichen planus amyloidosis [LPA]) has been described in some kindreds with MEN2A, predominantly those with pathogenic variants affecting exon 11 and codon 634 of RET, and some with pathogenic variants affecting codon 804. The diagnosis of CLA may precede the onset of clinically evident MTC. Patients with this clinical subtype of MEN2A develop pheochromocytomas and parathyroid hyperplasia with a similar frequency as those with classical MEN2A. (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2".)

MEN2A with Hirschsprung disease — HD is a motor disorder of the gut caused by the failure of neural crest cells to migrate completely during intestinal development. The resulting aganglionic segment of the colon fails to relax, causing a functional bowel obstruction. The co-occurrence of HD and MEN2A is predominantly associated with pathogenic variants involving codons 609, 611, 618, and 620 in exon 10 of RET (figure 1). In such patients, HD may be the first presentation of MEN2A. Patients with this variant of MEN2A develop MTC, pheochromocytomas, and parathyroid hyperplasia with a similar frequency as those with classical MEN2A. (See "Congenital aganglionic megacolon (Hirschsprung disease)".)

Familial medullary thyroid cancer — FMTC is a variant of MEN2A in which there is a strong predisposition to MTC, but not the other clinical manifestations of MEN2A (or 2B). The following criteria are used:

●More than 10 carriers in the kindred

●Multiple carriers or affected members age >50 years

●An adequate medical history, particularly in older family members

Multiple endocrine neoplasia type 2B — Individuals with MEN2B are at increased risk of MTC and pheochromocytoma, but parathyroid hyperplasia is not a feature of this disorder (table 2).

Patients with MEN2B tend to have mucosal neuromas, typically involving the lips and tongue, and intestinal ganglioneuromas. Disturbances of colonic function are common, including chronic constipation and megacolon. Many of these patients have developmental challenges, a Marfanoid habitus, and myelinated corneal nerves. MEN2B is typically associated with the methionine to threonine (p.Met918Thr) missense variant within the activation segment of RET kinase in exon 16 of the gene.

MANAGEMENT

Pathogenic variant in RET — Optimal management for individuals with a pathogenic variant in RET involves a multidisciplinary team (see 'Locating an expert' below). The location of the pathogenic variant within the gene is important and a genotype-phenotype correlation is well established. Patients can be classified into highest risk, high risk, and moderate risk with timing of surgery adjusted accordingly (table 3 and table 4).

Medullary thyroid cancer

Screening and prophylactic thyroidectomy — Virtually all patients with MEN2 develop clinically significant medullary thyroid cancer (MTC), often early in life. Individuals with a pathogenic RET variant should be screened for MTC with annual physical examination, neck ultrasound, and measurement of serum calcitonin from an early age. Prophylactic thyroidectomy should be performed before MTC develops or when it is still confined to the thyroid gland. The suggested timing of thyroidectomy is based upon evidence of age-dependent and codon-specific progression of early MTC (table 3). As mentioned above, RET variants can be categorized as highest, high, and moderate risk, referring to the potential risk for local and distant MTC metastases at an early age. The table summarizes risk of MTC with different RET variants, age to initiate monitoring for MTC, and age recommendations for performing prophylactic thyroidectomy (table 3).

Patients with MTC — For patients with MEN2 with MTC, total thyroidectomy is recommended. (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Medullary thyroid cancer' and "Approach to therapy in multiple endocrine neoplasia type 2", section on 'Medullary thyroid cancer'.)

Pheochromocytoma screening — Screening for pheochromocytoma is mandatory in all patients with MEN2. In particular, screening is indicated before thyroidectomy and in patients who are considering pregnancy to avoid a potential hypertensive crisis. The surgical management of unilateral and bilateral pheochromocytomas is discussed in detail separately (table 4). (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Pheochromocytoma' and "Approach to therapy in multiple endocrine neoplasia type 2", section on 'Pheochromocytoma'.)

Primary hyperparathyroidism in MEN2A — Screening for primary hyperparathyroidism with (ionized) calcium or serum calcium with albumin and intact parathyroid hormone (PTH) is recommended in patients with MEN2A. The age to begin screening (11 to 16 years) depends on the location of the pathogenic variant; screening is typically commenced at the same age as screening for pheochromocytoma (table 4). When the diagnosis of MEN2A-related MTC is established, we recommend measuring serum calcium to rule out hyperparathyroidism requiring concomitant surgical intervention. Indications for surgical intervention are discussed in detail separately. (See "Approach to therapy in multiple endocrine neoplasia type 2", section on 'Primary hyperparathyroidism' and "Primary hyperparathyroidism: Management".)

Hirschsprung disease — The treatment for HD is surgical resection of the aganglionic segment of bowel. (See "Congenital aganglionic megacolon (Hirschsprung disease)", section on 'Management'.)

Cutaneous lichen amyloidosis — There is no effective treatment for cutaneous amyloidosis.

Variant of uncertain significance (VUS) or negative genetic testing

●Negative genetic testing for a known familial pathogenic variant in RET – Negative testing for a known familial pathogenic variant in RET very likely excludes MEN2, with caveats noted above. (See 'How to read the report' above.)

●Negative genetic testing if familial RET variant unknown – If MEN2 is suspected based on personal or family history and a familial variant in RET has not been characterized, then negative testing of RET cannot be used to exclude the disorder. Consultation with a genetics expert is advised to determine the next steps, which may include gene panel testing for other genes or more extensive testing of RET. Biochemical testing can also be performed to detect MEN2-related tumors and includes testing serum calcitonin (with or without pentagastrin or calcium stimulation), plasma fractionated metanephrines, and serum calcium. If biochemical testing is used, then yearly testing starting at age five and continuing until at least age 35 years (or until a positive test occurs) is necessary. (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'When RET mutation is unknown'.)

●Variant of uncertain significance (VUS) – A VUS means the pathogenicity of the variant has not been determined. Management is based on personal and family history of MEN2 manifestations. Individuals with a VUS may benefit from consultation with an expert in MEN2 or a genetics expert to assist in determining the significance of the variant.

First-degree relatives — All first-degree relatives of an individual with a pathogenic variant in RET should be offered genetic counseling and testing for the variant. The parents of the proband should be tested if future childbearing is possible. It is possible that a parent may be affected but undiagnosed. It is also possible that the individual has a de novo germline pathogenic variant and the parent may be unaffected (algorithm 1). (See 'RET gene' above.)

MEN2 is inherited as an autosomal dominant trait. Each child of an affected parent has a 50 percent chance of inheriting the RET variant and being at risk for developing MEN2. Genetic testing should be performed at birth or very soon thereafter to determine the surveillance that is needed. Early diagnosis by screening "at-risk" family members in MEN2 kindreds is essential because MTC is a life-threatening disease that can be cured or prevented by early thyroidectomy.

Reproductive counseling should be provided for affected individuals to discuss reproductive options. Some may elect to conceive using donor gametes or in vitro fertilization (IVF) with preimplantation genetic testing (PGT). (See "In vitro fertilization: Overview of clinical issues and questions", section on 'When are donor oocytes used?' and "Donor insemination" and "Preimplantation genetic testing".)

RESOURCES

Information about MEN2

●UpToDate topics

•Genetics – (See "Classification and genetics of multiple endocrine neoplasia type 2".)

•Clinical features and diagnosis – (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2" and "Congenital aganglionic megacolon (Hirschsprung disease)".)

•Treatment – (See "Approach to therapy in multiple endocrine neoplasia type 2".)

•Guidelines – (See "Society guideline links: Medullary thyroid cancer".)

●MEN2 resources

•American Multiple Endocrine Neoplasia Support group

•National Organization of Rare Disorders (NORD)

Locating an expert

●Clinical geneticists – American College of Medical Genetics and Genomics

●Genetic counselors – National Society of Genetic Counselors. Genetic testing laboratories may also provide online or telephone access to a genetic counselor.

●National Institutes of Health (NIH) Cancer Genetics Services Directory