RET (MEN2) – risk management

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant condition caused by heterozygous activating (gain of function) pathogenic variants in the RET proto-oncogene. Information in this protocol is limited to specific RET pathogenic variants known to be associated with a clinical phenotype of MEN2. 

There are 2 clinical subtypes of MEN2:

1. MEN2A clinical subtype: Medullary thyroid carcinoma (MTC), with variable frequency of adrenal phaeochromocytoma (PC) and primary hyperparathyroidism (PHPT). 
2. MEN2B clinical subtype: MTC associated with syndromic features and increased risk of adrenal phaeochromocytoma.

• Individuals with a germline pathogenic variant in the RET gene (both MEN2 subtypes).

Exclusion criteria

• Individuals with inactivating (loss of function) pathogenic variants in the RET gene.
• First degree relatives (i.e. individuals at 50% risk) who have not yet had pathogenic variant testing; should first be encouraged to have testing as the only proven risk-reducing strategy is total thyroidectomy.
• Families with a clinical diagnosis of MEN2A or MEN2B, but where RET sequencing has not identified a pathogenic variant.*
• Families with MTC but no other features of MEN2 and where RET sequencing has not identified a pathogenic variant.*
• Individuals with a variant of uncertain significance.

*An individualised programme of screening may be appropriate, but this decision should be made in consultation with a specialist endocrinologist with expertise in the area.

There is a strong correlation between the location of the pathogenic variant within the RET gene, the penetrance and median age of tumour development (MTC, PC and PHPT), and the aggressiveness of MTC.^r 

The American Thyroid Association (ATA) risk classification of variants is based on MTC risk (Highest risk, High risk and Moderate risk).^r Refer to table below:

*For the MEN2B phenotype: 95% of patients have a M918T variant (ATA-HST); minority have A883F variant (ATA-H)

The choice of risk management strategy should take into account current age, other health issues and age-related cancer risk. Risks and benefits of interventions should be discussed with an experienced medical professional.

The impact of lifestyle on general cancer risks should be discussed e.g. exercise most days for at least 30 minutes at moderate or strenuous intensity, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure.

^^Clinically significant parathyroid disease is absent in MEN2B.

See also Measurement and tests for biogenic amines including information for patients who are having tests

• Hypothyroidism post thyroidectomy should be treated according to standard guidelines.
• 5-10% of patients with MEN2A and an activating RET pathogenic variant, have Hirschsprung’s disease. Management of the non-tumour features of MEN2A or MEN2B (including Hirschsprung's disease) is not covered by this document.

Medullary thyroid cancer (MTC)

Surgical 

In MEN2, early intervention with risk-reducing thyroidectomy has been shown to significantly lower the mortality associated with MTC. The strongest predictor of survival from MTC is stage of disease at diagnosis. Individuals should be referred to endocrine surgeons and endocrinologists familiar with the revised American Thyroid Association (ATA) guidelines^r to discuss the timing and extent of risk-reducing thyroidectomy.

Thyroidectomy is recommended by 1 year of age for ATA highest risk (ATA-HST) and by 5 years of age for ATA high risk (ATA-H) variants. In these variants, there is a narrow window of opportunity for curative thyroidectomy and early surgery is recommended.^rr

For patients with ATA moderate risk (ATA-MOD) variants, thyroidectomy is generally performed by 5 to 10 years of age. Recent guidelines suggest that surgery could be delayed until 10 to 15 years of age in some patients, but even then only if strict criteria are met, including normal annual calcitonin/neck ultrasound; less aggressive family history of MTC; regular attendance for surveillance and parental consent including the risk of developing MTC not cured by thyroidectomy.^r This decision should be individualised taking into account the family history of thyroid cancer, including age at diagnosis. The decision should also balance the risks of thyroidectomy at a younger age with the risks of delaying surgery, including loss to follow up and the risk of developing MTC that has extended beyond the thyroid at the time of diagnosis.^r

Surveillance

Post-operatively, the most recently published expert consensus recommends surveillance with calcitonin/CEA at 3 months, 6 months and 12 months, then annually thereafter if undetectable.^r

Adrenal phaeochromocytoma

Surveillance

Patients with MEN2-associated RET variants should have surveillance for phaeochromocytoma with either plasma free metanephrines or fractionated urine metanephrines. Link to further information on measurement of biogenic amines. Imaging is only required if a phaeochromocytoma is suspected biochemically and is NOT recommended for surveillance.

Expert consensus is that annual surveillance should commence by age 11 years in patients with ATA-HST and ATA-H variants and by age 16 years in patients with ATA-MOD variants, earlier if hypertensive.^r Less frequent surveillance could be considered in late adulthood (> 50 years of age) when the incidence of phaeochromocytoma falls depending on the ATA risk category.^r

Patients who have a unilateral phaeochromocytoma have a high risk of developing bilateral disease. When contralateral tumours do occur, most develop within 10 years of the first.^r

Parathyroid disease

Surveillance

Primary hyperparathyroidism is most strongly associated with codon 630 and 634 pathogenic variants and is less commonly seen with variants in other codons.^r Clinically significant primary hyperparathyroidism is rare in childhood.

The age to commence surveillance for primary hyperparathyroidism and the optimal screening interval are both unclear. The most recently published expert consensus recommends screening for primary hyperparathyroidism occur annually and start by age 11 years in children with ATA-H variants, and by age 16 years for ATA-MOD variants.^r Hypercalcaemia should also be excluded prior to thyroidectomy, for adequate surgical planning.

In patients with MEN2B the risk of primary hyperparathyroidism is no higher than that of the general population and surveillance is not required.    

First degree blood relatives (parents/brothers/sisters/children) are at up to 50% risk of having inherited the pathogenic variant. More distant relatives may also be at risk of inheriting the pathogenic variant. Genetic relatives should be referred to a clinical genetics service or familial cancer centre to discuss predictive genetic testing.

RET pathogenic variant carriers of childbearing age should be offered genetic counselling, including the options of pre-implantation genetic diagnosis and prenatal testing.

Informing family members about hereditary cancer.

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Bibliography

Brandi, M. L., R. F. Gagel, A. Angeli, et al. 2001. "Guidelines for diagnosis and therapy of MEN type 1 and type 2." J Clin Endocrinol Metab 86(12):5658-5671.

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This is a consensus statement from an international group, mostly of clinical endocrinologists. MEN1 and MEN2 are hereditary cancer syndromes. The commonest tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of entero-pancreatic hormones, except insulin. The roles for surgery of most entero-pancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial medullary thyroid cancer (MTC). They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy.

Eisenhofer, G., J. W. Lenders, H. Timmers, et al. 2011. "Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma." Clin Chem 57(3):411-420.

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BACKGROUND: Pheochromocytomas are rare catecholamine-producing tumors derived in more than 30% of cases from mutations in 9 tumor-susceptibility genes identified to date, including von Hippel-Lindau tumor suppressor (VHL); succinate dehydrogenase complex, subunit B, iron sulfur (Ip) (SDHB); and succinate dehydrogenase complex, subunit D, integral membrane protein (SDHD). Testing of multiple genes is often undertaken at considerable expense before a mutation is detected. This study assessed whether measurements of plasma metanephrine, normetanephrine, and methoxytyramine, the O-methylated metabolites of catecholamines, might help to distinguish different hereditary forms of the tumor. METHODS: Plasma concentrations of O-methylated metabolites were measured by liquid chromatography with electrochemical detection in 173 patients with pheochromocytoma, including 38 with multiple endocrine neoplasia type 2 (MEN 2), 10 with neurofibromatosis type 1 (NF1), 66 with von Hippel-Lindau (VHL) syndrome, and 59 with mutations of SDHB or SDHD. RESULTS: In contrast to patients with VHL, SDHB, and SDHD mutations, all patients with MEN 2 and NF1 presented with tumors characterized by increased plasma concentrations of metanephrine (indicating epinephrine production). VHL patients usually showed solitary increases in normetanephrine (indicating norepinephrine production), whereas additional or solitary increases in methoxytyramine (indicating dopamine production) characterized 70% of patients with SDHB and SDHD mutations. Patients with NF1 and MEN 2 could be discriminated from those with VHL, SDHB, and SDHD gene mutations in 99% of cases by the combination of normetanephrine and metanephrine. Measurements of plasma methoxytyramine discriminated patients with SDHB and SDHD mutations from those with VHL mutations in an additional 78% of cases. CONCLUSIONS: The distinct patterns of plasma catecholamine O-methylated metabolites in patients with hereditary pheochromocytoma provide an easily used tool to guide cost-effective genotyping of underlying disease-causing mutations.

Frank-Raue, K., L. A. Rybicki, Z. Erlic, et al. 2011. "Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10." Hum Mutat 32(1):51-58.

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Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for clinical-risk profiles. Presentation, age-dependent penetrance, and stage at presentation of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism were studied. A total of 340 subjects from 103 families, age 4-86, were registered. There were 21 distinct single nucleotide germline mutations located in codons 609 (45 subjects), 611 (50), 618 (94), and 620 (151). MTC was present in 263 registrants, pheochromocytoma in 54, and hyperparathyroidism in 8 subjects. Of the patients with MTC, 53% were detected when asymptomatic, and among those with pheochromocytoma, 54%. Penetrance for MTC was 4% by age 10, 25% by 25, and 80% by 50. Codon-associated penetrance by age 50 ranged from 60% (codon 611) to 86% (620). More advanced stage and increasing risk of metastases correlated with mutation in codon position (609-- >620) near the juxtamembrane domain. Our data provide rigorous bases for timing of premorbid diagnosis and personalized treatment/prophylactic procedure decisions depending on specific RET exon 10 codons affected

Milos, I. N., Frank-Raue K, Wohllk N, et al. 2008. "Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp (TGC>TGG) mutation." Endocr Relat Cancer 15(4):1035-1041

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RET testing in multiple endocrine neoplasia type 2 for molecular diagnosis is the paradigm for the practice of clinical cancer genetics. However, precise data for distinct mutation-based risk profiles are not available. Here, we survey the clinical profile for one specific genotype as a model, TGC to TGG in codon 634 (C634W). By international efforts, we ascertained all available carriers of the RET C634W mutation. Age at diagnosis, penetrance, and clinical complications were analyzed for medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism (HPT), as well as overall survival. Our series comprises 92 carriers from 20 unrelated families worldwide. Sixty-eight subjects had MTC diagnosed at age 3-72 years (mean 29). Lymph node metastases were observed in 16 subjects aged 20-72 and distant metastases in 4 subjects aged 28-69. Forty-one subjects had pheochromocytoma detected at age 18-67 (mean 36). Amongst the 28 subjects with MTC and pheochromocytoma, six developed pheochromocytoma before MTC. Six subjects had HPT diagnosed at age 26-52 (mean 39). Eighteen subjects died; of the 16 with known causes of death, 8 died of pheochromocytoma and 4 of MTC. Penetrance for MTC is 52% by age 30 and 83% by age 50, for pheochromocytoma penetrance is 20% by age 30 and 67% by age 50, and for HPT penetrance is 3% by age 30 and 21% by age 50. These data provide, for the first time, RET C634W-specific neoplastic risk and age-related penetrance profiles. The data may facilitate risk assessment and genetic counseling

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