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Cancer Predisposition

Familial medullary thyroid carcinoma

FMTC is a rare, inherited cancer predisposition syndrome primarily affecting the thyroid gland. It is characterised by a high lifetime risk of medullary thyroid cancer, which can develop at various ages.

Autosomal dominant Cancer Predisposition Tier B OMIM:155240
Rare
Prevalence
Population estimate
50%
Inheritance
Autosomal dominant - chance of passing to each child
1
Associated genes
RET

Available at Jeen Health

Clinical tests that include this

Cancer Screening panel
RET - 1 of 50 genes on this panel
Hereditary cancer predisposition screening

Overview

Familial medullary thyroid carcinoma (FMTC) is a hereditary condition that significantly increases an individual's likelihood of developing medullary thyroid cancer (MTC). MTC originates from the parafollicular C cells of the thyroid gland, which are responsible for producing the hormone calcitonin. Unlike other types of thyroid cancer, MTC can often run in families, hence the term 'familial' [PMID:33678087].

FMTC is considered a form of multiple endocrine neoplasia type 2 (MEN2), specifically MEN2A or MEN2B, but without the involvement of other endocrine glands typically seen in those broader syndromes. This means that individuals with FMTC primarily experience medullary thyroid cancer, distinguishing it from the more extensive MEN2 syndromes that also include tumours of the adrenal and parathyroid glands. The condition is rare, and its exact prevalence is not well established.

Symptoms & clinical features

The primary clinical feature of FMTC is medullary thyroid cancer. This cancer often does not cause noticeable symptoms in its early stages. When symptoms do appear, they can be varied and may include a lump or swelling in the neck, which is usually painless. Some individuals might experience difficulty swallowing (dysphagia) or a persistent hoarse voice due to the tumour pressing on nearby structures [PMID:33678087].

In some cases, individuals with MTC may experience diarrhoea or flushing, which are thought to be related to the increased production of calcitonin and other hormones by the cancer cells. These systemic symptoms typically occur in more advanced stages of the disease. Regular screening is important for individuals at risk of FMTC to detect the cancer early, often before symptoms develop.

Video: Is cancer in your genes?

Affected organs

The thyroid gland is the main organ affected in familial medullary thyroid carcinoma. The thyroid is a butterfly-shaped gland located at the base of the neck, playing a crucial role in metabolism by producing thyroid hormones. In FMTC, the parafollicular C cells within the thyroid gland undergo uncontrolled growth, leading to the formation of medullary thyroid cancer.

While FMTC is defined by its primary impact on the thyroid, it is part of a broader spectrum of conditions (MEN2) that can affect other endocrine glands. However, by definition, FMTC specifically refers to cases where only medullary thyroid cancer occurs, without the pheochromocytomas (adrenal gland tumours) or parathyroid adenomas/hyperplasia seen in other forms of MEN2.

Multiple body systems
Multiple body systems
Systemic involvement
Cellular impact
Cellular impact
Mechanism at cellular level

Risks & severity

Individuals with FMTC have a very high lifetime risk of developing medullary thyroid cancer, often approaching 100% if not managed proactively. The age of onset for MTC in FMTC can vary significantly, with some individuals developing the cancer in childhood and others later in adulthood. The severity of MTC can range from slow-growing and treatable to more aggressive forms that can spread to other parts of the body (metastasise).

Early detection through genetic testing and subsequent prophylactic thyroidectomy (surgical removal of the thyroid) significantly reduces the risk of developing MTC or improves outcomes if cancer has already begun to develop. Without early intervention, MTC can be life-threatening. The specific genetic change (pathogenic variant) identified can sometimes influence the typical age of onset and the aggressiveness of the cancer, guiding clinical surveillance and management strategies.

Genetic causes

Familial medullary thyroid carcinoma is caused by specific pathogenic variants in the RET gene. The RET gene provides instructions for making a protein known as the 'RET receptor tyrosine kinase'. This protein is located on the surface of cells and acts as a receptor, receiving signals from outside the cell. These signals are crucial for cell growth, survival, and differentiation [PMID:36009848].

Normally, the RET protein is vital for the development and function of several body systems, including the nervous system and kidneys. Pathogenic variants in RET lead to a protein that is overactive or constitutively 'switched on', even without external signals. This uncontrolled signalling promotes abnormal cell growth and division, specifically in the parafollicular C cells of the thyroid, resulting in medullary thyroid cancer. Different pathogenic variants in RET are associated with varying risks and clinical presentations of MTC.

  • RET
    ret proto-oncogene
    The RET gene provides instructions for a receptor tyrosine kinase protein involved in cell signalling, crucial for the development of various nerve cells, kidneys, and spermatogenesis.

Inheritance pattern

Familial medullary thyroid carcinoma is inherited in an autosomal dominant pattern. This means that a person only needs to inherit one copy of the altered RET gene from either parent to be at an increased risk of developing the condition. If a parent has a pathogenic variant in the RET gene, each of their children has a 50% chance (one in two) of inheriting the variant and therefore being at increased risk for FMTC.

inheriting the altered gene means an increased risk, but not everyone who inherits the variant will develop cancer at the same age or with the same severity. Genetic counselling can help families understand this inheritance pattern and the implications for both affected individuals and their relatives.

♀ Affected parent 1 altered copy ♂ Unaffected parent 2 typical copies Affected Unaffected Unaffected Affected Affected Carrier Unaffected Circles = females · Squares = males

Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.

Diagnosis & testing

The diagnosis of familial medullary thyroid carcinoma is typically confirmed through genetic testing for pathogenic variants in the RET gene. This testing is often recommended for individuals with a personal history of medullary thyroid cancer, particularly if they have a family history of the condition. Genetic testing can also be offered to asymptomatic family members who are at risk due to a known pathogenic variant in their family [PMID:33678087].

In the UK, suspected cases of inherited cancer predisposition, including FMTC, are typically referred to Clinical Genetics services by a GP or specialist. Genetic testing for RET variants falls under NHS Genomic Medicine Service (GMS) pathways, with specific R-codes for testing, such as R210 Medullary Thyroid Cancer. Diagnosis involves a blood sample, from which DNA is extracted and analysed for specific changes in the RET gene. Pre-symptomatic testing in at-risk children is also a critical part of managing FMTC.

Management & lifestyle

Management of familial medullary thyroid carcinoma focuses on early detection and intervention to prevent or treat medullary thyroid cancer. For individuals found to carry a pathogenic RET variant, regular surveillance is crucial, often involving blood tests to measure calcitonin levels, which can be an early indicator of MTC. Ultrasound examinations of the neck may also be used to monitor the thyroid gland.

Prophylactic total thyroidectomy, the surgical removal of the entire thyroid gland, is often recommended for individuals with a pathogenic RET variant before cancer develops. The timing of this surgery depends on the specific RET variant identified, as some variants are associated with earlier onset and more aggressive disease [PMID:36009848]. Following thyroidectomy, individuals will require lifelong thyroid hormone replacement therapy. Management plans are individualised and developed in consultation with a multidisciplinary team, including endocrinologists, surgeons, and clinical geneticists, within the NHS framework. Genetic counsellors provide essential support and information throughout this process.

UK care pathway

In the UK, individuals suspected of having familial medullary thyroid carcinoma, or those with a family history, will typically be referred to their local NHS Clinical Genetics service. This referral can be initiated by a GP or another specialist. The Clinical Genetics team will assess family history, discuss the implications of genetic testing, and arrange for appropriate investigations.

Genetic testing for inherited forms of medullary thyroid cancer, specifically involving the RET gene, is available through the NHS Genomic Medicine Service (GMS). This testing is typically covered under specific R-codes, such as R210 (Medullary Thyroid Cancer). Following a diagnosis, ongoing care is managed by a multidisciplinary team, with genetic counsellors providing crucial support and information to help patients and families navigate their condition and make informed decisions.

Frequently asked questions

What is the difference between FMTC and MEN2?

Familial medullary thyroid carcinoma (FMTC) is a type of Multiple Endocrine Neoplasia type 2 (MEN2) where individuals primarily develop medullary thyroid cancer. Other forms of MEN2, like MEN2A and MEN2B, include MTC along with tumours in other glands, such as the adrenal or parathyroid glands.

If I have FMTC, will my children get it?

FMTC is inherited in an autosomal dominant pattern. This means if you have the condition, each of your children has a 50% chance of inheriting the altered gene that increases their risk for FMTC. Genetic counselling can provide more personalised information.

Can medullary thyroid cancer be prevented in FMTC?

While the cancer itself cannot be absolutely prevented, early diagnosis of the genetic change allows for proactive management. Prophylactic thyroidectomy, the surgical removal of the thyroid gland before cancer develops, is often recommended for individuals with a pathogenic RET variant to significantly reduce their lifetime risk.

What kind of surveillance will I need if I have FMTC?

Surveillance typically involves regular blood tests to check calcitonin levels, which can be an early marker for medullary thyroid cancer. Neck ultrasound scans may also be performed periodically to monitor the thyroid gland for any changes. The specific surveillance schedule is tailored to each individual.

Where can I get support if I or a family member has FMTC?

In the UK, your NHS Clinical Genetics service can provide information and support, including access to genetic counsellors. Support groups and patient organisations can also offer valuable resources and peer support for individuals and families affected by rare conditions like FMTC.

References

  1. Guilmette J, Nosé V. Hereditary and familial thyroid tumours. Histopathology. 2018. PMID: 29239041
  2. Guyétant S, Bléchet C, Saint-André JP. C-cell hyperplasia. Annales d'endocrinologie. 2006. PMID: 16840909
  3. Barletta JA, Nosé V, Sadow PM. Genomics and Epigenomics of Medullary Thyroid Carcinoma: From Sporadic Disease to Familial Manifestations. Endocrine pathology. 2021. PMID: 33492588
  4. Moo-Young TA, Traugott AL, Moley JF. Sporadic and familial medullary thyroid carcinoma: state of the art. The Surgical clinics of North America. 2009. PMID: 19836492
  5. Ordookhani A, Motazedi A, Burman KD. Thrombosis in Thyroid Cancer. International journal of endocrinology and metabolism. 2018. PMID: 29696039
  6. Iacovazzo D, Begalli F, Suleyman O. Familial medullary thyroid carcinoma secondary to an SLC30A9 intragenic deletion and translation reinitiation. medRxiv : the preprint server for health sciences. 2026. PMID: 41847600
  7. Matrone A, Gambale C, Prete A. Sporadic Medullary Thyroid Carcinoma: Towards a Precision Medicine. Frontiers in endocrinology. 2022. PMID: 35422765
  8. Nosé V. Familial non-medullary thyroid carcinoma: an update. Endocrine pathology. 2008. PMID: 18931957
Educational content. This page is not medical or genetic advice, is not individually reviewed by a clinician for each reader, and should not replace a consultation with a qualified healthcare professional or genetic counsellor.