Key facts
- Familial medullary thyroid cancer (FMTC) is an inherited condition and a subtype of MEN2 (multiple endocrine neoplasia type 2), a hereditary endocrine cancer syndrome.
- Individuals with FMTC have a high probability of developing medullary thyroid cancer (MTC) with a lower probability (<5%) of developing the other specific endocrine tumours (phaeochromocytoma or parathyroid hyperplasia) usually associated with MEN2.
- FMTC accounts for 10-20% of all MEN2 cases.
- Genetic testing is essential for all MTC patients, even if there is no known family history.
- The age of onset of FMTC is usually later than in other types of MEN2 (typically middle age).
- FMTC is an autosomal dominant condition, and occurs due to genetic variants in the RET proto-oncogene.
- Approximately 80% of individuals with a RET genetic variant will develop medullary thyroid cancer at some point in their lives.
- Early diagnosis, treatment and management of the condition improves outcome and quality of life.
- The prevalence of MEN2 (including FMTC) is estimated to be between 1 and 9 in 100,000 individuals.
- Prenatal counselling and genetic testing are available.
Clinical features
- The clinical features of FMTC are due to the onset of medullary thyroid cancer. Features may include:
- a neck lump or neck pain; and
- diarrhoea due to raised calcitonin levels.
Diagnosis of medullary thyroid cancer (MTC)
- ultrasound or CT imaging confirming a suspicious node/mass;
- fine needle aspiration, or other histology confirming MTC; and
- raised calcitonin levels.
Genetic basis and genetic testing
- FMTC is caused by genetic variants in the RET gene, which are inherited in an autosomal dominant manner. Children of an affected individual have a 50% (one-in-two) chance of inheriting the gene alteration.
- Due to the particular genetic variants that cause FMTC, the patient has a high probability of developing MTC and a low probability of developing other endocrine tumours.
- Genetic testing can detect over 95% of variants in the RET gene.
- Indications for genetic counselling and testing include:
- a confirmed diagnosis of medullary thyroid cancer;
- a confirmed RET genetic variant in a blood relative;
- predictive testing for parents, siblings and offspring of someone with a confirmed RET genetic variant. (For children, this would involve a cord blood sample at birth, or testing before four or five years of age. For children older than five years of age, genetic testing is recommended as matter of urgency); and
- prenatal diagnosis.
- Genetic testing is available in the UK and is usually provided through specialist clinics or regional genetic centres.
Clinical management
- Patients with FMTC should always be managed by a specialist multidisciplinary team consisting of an endocrinologist, an experienced thyroid surgeon (skilled at operating on medullary thyroid cancers) and a clinical geneticist and genetic counsellor.
- Annual screening is recommended, and may include the following tests:
Individuals with medullary thyroid cancer
- annual plasma calcitonin level;
- annual neck and thorax MRI; and
- somatostatin receptor nuclear medicine imaging, where available.
Individuals with phaeochromocytoma
- annual 24-hour urine or plasma metanephrines measurement;
- annual blood pressure; and
- abdominal scan if metanephrines become elevated.
Individuals with primary hyperparathyroidism
- annual serum calcium test.
Pregnant individuals
- up to date phaeochromocytoma screening; and
- referral to a specialist endocrine antenatal clinic.
- tyrosine kinase inhibitors as promising potential treatments for patients with unresectable (unable to be removed with surgery), locally advanced or metastatic MTC.
Treatment of medullary thyroid cancer
- total thyroidectomy and neck dissection, with removal of lymph nodes as required, followed by lifelong thyroid hormone replacement;
- prophylactic thyroidectomy in children who are identified as carrying RET gene variants, to be considered at an early age, depending on the exact variant identified.
- tyrosine kinase inhibitors as promising potential treatments for patients with unresectable (unable to be removed with surgery), locally advanced or metastatic MTC.
Direction to further reading, society guidelines and patient groups
This information is intended for educational use and was current in January 2020. For clinical management, it is recommended that local guidelines and protocols are used.
Produced in collaboration with Birmingham Women’s NHS Foundation Trust’s Clinical Genetics department and Imperial College Healthcare NHS Trust.
