Multiple endocrine neoplasia type 2

Multiple endocrine neoplasia type 2 (MEN2) can be subclassified into MEN2A and MEN2B. MEN2A is inherited in an autosomal dominant pattern, and is characterised by a predisposition to medullary thyroid carcinoma (MTC), phaeochromocytoma and hyperparathyroidism. MEN2B is also an autosomal dominant condition, and predisposes to MTC, phaeochromocytoma, aero-digestive ganglioneuromatosis and skeletal anomalies (such as marfanoid body habitus, pes cavus, pectus excavatum, thickened lips and neuromas affecting the tongue, high-arched palate, scoliosis and slipped capital femoral epiphyses).

• When it comes to genotype-phenotype correlation in MEN2, long-term observational studies have facilitated an understanding that specific RET variants cause more severe phenotypes (in, for example, the onset and severity of MTC). This has facilitated the classification of specific variants in the RET gene according to the aggressive nature of the MTC, which is the most penetrant phenotype.
• RET gene variants are classified into the categories ‘highest’, ‘high’ and ‘moderate’, depending on the typical associated MTC risk.
• This classification of RET variants informs the age at which genomic testing and prophylactic thyroidectomy should be considered in affected children (table 1).

Penetrance of clinical features

• Without prophylaxis, MTC occurs in the majority of patients with MEN2. The age of onset varies from infancy to early adulthood, depending on the specific RET gene variant.
• Phaeochromocytoma penetrance is also predicted by the RET gene variant, with the highest penetrance observed in patients with highest-risk and high-risk RET gene variants (table 1). Phaeochromocytomas can be bilateral in patients with MEN2.
• Primary hyperparathyroidism occurs in patients with MEN2A, with a penetrance of 10%–30%. Patients with MEN2A may also develop cutaneous lichen amyloidosis and Hirschsprung disease.
• Patients with MEN2B have other specific clinical manifestations, including:
  • alacrima (tearless crying);
  • thickened and everted eyelids;
  • skeletal anomalies, including:
    • marfanoid body habitus;
    • pes cavus;
    • pectus excavatum;
    • thickened lips and neuromas affecting the tongue;
    • high-arched palate;
    • scoliosis; and
    • slipped capital femoral epiphyses); and
    • aerodigestive ganglioneuromatosis.

Table 1: Overview of MEN2-related conditions according to American Thyroid Association (ATA) risk category

*RET variants are listed in the table by the amino acid change. For example, M918T corresponds to a change from methionine (M) to threonine (T) at codon 918. See this table for a list of amino acids and their corresponding single-letter codes.

• Constitutional (germline) pathogenic gain-of-function variants in the RET proto-oncogene, located on chromosome 10, are the molecular driver of MEN2.
• For information about genomic testing, see Patient with endocrine neoplasia and Patient with medullary thyroid carcinoma.

Genomic testing is the principle diagnostic test for MEN2. The condition should be considered in any patient presenting with medullary thyroid carcinoma, unilateral or bilateral phaeochromocytoma or primary hyperparathyroidism at a young age (<45 years), or a family history of any of the above.

Patients with MEN2B have other specific clinical manifestations that should prompt confirmatory molecular testing, including:

• alacrima (tearless crying);
• thickened and everted eyelids; and/or
• skeletal anomalies, including:
  • marfanoid body habitus;
  • pes cavus;
  • thickened lips and neuromas affecting the tongue;
  • high-arched palate;
  • scoliosis;
  • slipped capital femoral epiphyses; and/or
  • aerodigestive ganglioneuromatosis.

• MEN2 is inherited in an autosomal dominant pattern.
• The child of an individual with MEN2 has a 50% chance of inheriting the pathogenic RET variant. The type of clinical surveillance, the age of testing and the age at which a prophylactic thyroidectomy should be offered to proven carriers all vary depending on the risk category of the RET variant (table 1).
• Prenatal and preimplantation genetic testing is available to individuals with MEN2.

• Management of MTC, phaeochromocytoma or primary hyperparathyroidism in patients with MEN2 should be led by a specialist multidisciplinary team.
• Prophylactic thyroidectomy should be offered in childhood or if calcitonin becomes elevated based on the RET gene risk (table 1).
• For patients diagnosed with MEN2 in adulthood, the thyroid should be assessed using a combination of thyroid ultrasound, serum calcitonin and fine needle aspiration before planning thyroid surgery, and a phaeochromocytoma should be excluded before surgery is undertaken.
• Patients with MEN2 should be offered surveillance for phaeochromocytoma and primary hyperparathyroidism as per their RET gene risk (table 1).
• Patients with phaeochromocytoma should be managed by an experienced team, and can be considered for a cortical sparing surgery as they are at risk of developing a metachronous phaeochromocytoma.

Note that management of individuals diagnosed with MEN2 who are not showing symptoms may differ from management of those presenting symptomatically.

For clinicians

• Genomics England: Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory

References:

• Neumann HPH, Tsoy U, Bancos I and others. ‘Comparison of pheochromocytoma-specific morbidity and mortality among adults with bilateral pheochromocytomas undergoing total adrenalectomy vs cortical-sparing adrenalectomy’. Journal of the American Medical Association 2019: volume 2, issue 8. DOI: 10.1001/jamanetworkopen.2019.8898
• Wells SA Jr, Asa SL, Henning D and others. ‘Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma’. Thyroid 2015: volume 25, issue 6, pages 567–610. DOI: 10.1089/thy.2014.0335

For patients

• Association for Multiple Endocrine Neoplasia Disorders (AMEND)
• AMEND: Starting a family: Your choices (online booklet, 34 pages)
• ThyCa: Thyroid Cancer Survivors’ Association Inc