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PATIENT INFORMATION

Familial Medullary Thyroid Cancer

(FMTC)

MMEENN 22//FFMMTTCC SSUUPPPPOORRTT

Tel: 01892 525308 (Jo) (9am – 8pm)

Email: jo.grey@amend.org.uk

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[Publication last updated November 06]

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Table of Contents

Page No.

2 Table of Contents and Foreword

3-4 What is FMTC?

5 How is FMTC Diagnosed?

6 Medullary Thyroid Cancer

7 Testing for Medullary Thyroid Cancer

7-8 Treating Medullary Thyroid Cancer

9-10 Children and FMTC

11-12 Genetic Testing Explained

13 Useful Organisations Useful Information

14 AMEND Publications List About AMEND Comments

15 Acknowledgements And References

This book has been written for patients by patients with the help of a medical advisory panel. The aim of this book is to answer those questions, sometimes in great detail, that one may come across during a lifetime of living with FMTC. It is not for use in self-diagnosis. It contains detailed information on tests, surgery and potential symptoms associated with FMTC. However, it is possible that not all of this information will be relevant to you. This book is not intended to replace clinical care decisions and you should always discuss any concerns you may have carefully with your specialist. Every care has been taken to ensure that the information contained in this book is accurate, nevertheless, AMEND cannot accept responsibility for any clinical decisions.

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What is Familial Medullary Thyroid Cancer?

Familiary Medullary Thyroid Cancer, or FMTC, is a rare inherited form of cancer of the thyroid gland. FMTC is often included in a group of rare genetic disorders called Multiple Endocrine Neoplasia Type 2 (MEN2), the other types being MEN2a and MEN2b. The other MEN disorders occur when more than one gland of the body’s endocrine (gland) system develop a tumour. In MEN2a & b benign tumours of the adrenal and parathyroid glands may occur, and medullary thyroid cancer (MTC) in the thyroid gland is virtually always present. The affected glands produce abnormally increased amounts of hormones, the body’s chemical messengers, which in turn cause a variety of different symptoms

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What is Familial Medullary Thyroid Cancer? (Continued)

FMTC differs considerably from the other MEN disorders in that only the thyroid gland is affected, however, like MEN2, FMTC is an inherited disorder caused by a fault on a gene. In 1993, the gene responsible for FMTC and MEN2, the RET proto-oncogene, was identified by Professor Bruce Ponder and his colleagues from Cambridge in the UK. FMTC occurs in the thyroid in the neck (mmeedduullllaarryy tthhyyrrooiidd ccaanncceerr). The remainder of this information leaflet details the current thinking on appropriate tests, treatment and medications for FMTC. Treatment for FMTC starts with the monitoring of hormone levels using blood tests and scans of the neck, sometimes leading to the surgical removal of the tumour. Table 1 below details the current medical strategies for testing FMTC patients. See Testing for Medullary Thyroid Cancer section for more details on the tests themselves.

Table 1. (Recommended testing programme for FMTC patients)

DISEASE CLINICAL TESTING ACCORDING TO SPECIFIC RET GENE MUTATION WITHIN THE FAMILY

FREQUENCY

Medullary Thyroid Cancer (MTC)

Plasma calcitonin (CT) levels

Annual + pre/post total thyroidectomy

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How is FMTC Diagnosed?

A diagnosis of FMTC may be arrived at if the patient falls into one of two different categories:

1. Familial FMTC ; where the patient has a tumour, and there exists a family history of relatives with FMTC;

2. FMTC carrier; where a patient is recognised as carrying the genetic mutation responsible for FMTC, even if there is no tumour present in that patient at that time. A FMTC carrier is identified by positive DNA test (see Genetic Testing Explained). This test is usually performed for children of known affected families or if a patient has presented with MTC and who may therefore be the first identified of a new affected family. The discovery of the FMTC gene has helped to identify individuals at risk of inheriting FMTC, and to reassure other family members who are not at risk.

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All FMTC patients will develop medullary thyroid cancer (MTC) by age 40. Its level of aggressiveness is determined by which codon of the RET gene is mutated (see Genetic Testing Explained), although FMTC codons give rise to a less aggressive and slower growing form of MTC compared to the sporadic form. The thyroid is situated at the front of the neck. This gland produces 3 hormones; thyroxine and triiodothyronine, which are essential for maintaining the body’s metabolism and mental and physical development, and calcitonin, which is a calcium regulating hormone, though its excess is not associated with any hormone problems and its lack does not cause high blood calcium levels.

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radiation treatments. Nevertheless, it is

MTC occurs in the calcitonin-producing cells (parafollicular or C-cells) of the thyroid. The precursor to MTC is called C-cell hyperplasia, where there is abnormal growth of the normal C-cells and overproduction of calcitonin. MTC usually develops over a number of years from this abnormal growth but can spread early on to nearby lymph nodes. If the thyroid and nearby lymph nodes are surgically removed while the C-cell hyperplasia or cancer is still contained within the thyroid (total thyroidectomy and central lymph node dissection), a patient is usually cured. If, after surgery, calcitonin levels are still raised, this indicates that the cancer has spread (metastatic) or has not been completely removed, and so further surgery and therapies are used to control it. As yet there is no definitive cure for metastatic MTC, as it rarely responds well to regular chemotherapy orusually slow growing and may often be managed effectively and without symptoms for many years. Due to the earlier detection of FMTC made possible by the genetic test, and the high probability that an affected patient will develop MTC, thyroidectomy is now performed in affected children. This course of action may be responsible for drastically reducing the number of deaths in MEN2/FMTC patients from metastatic MTC from 15-20% to just 5%.

Medullary Thyroid Cancer (MTC)

“My son had his thyroidectomy at age 3. We were so terrified but everyone at the hospital was great. He was sitting up tucking into a jam sandwich within

an hour of waking up from the anaesthetic and running around in the playroom in under 2 hours – he put us

adults to shame!”

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Baseline Calcitonin

A simple blood test to detect calcitonin levels [NB: once drawn, the blood must be taken immediately and on ice to a chilled centrifuge in the lab]

Pentagastrin Stimulation

Provocative blood test to detect calcitonin levels. Overnight fasting required. A substance called pentagastrin is injected first and causes momentary side effects in the patient, including flushing, nausea and a feeling of needing to use the toilet. Samples are then taken at timed intervals of 1, 2, 3, 5 and 10 minutes [samples must be taken immediately and on ice to the lab]

Ultrasound with Fine Needle Aspiration (FNA)

A painless scan of the neck using a probe. The images then guide the insertion of a needle to biopsy (sample) thyroid tissue.

Testing for C-cell Hyperplasia & MTC

Treating MTC

Once a diagnosis of FMTC has been made, a staging ultrasound scan of the neck should be undertaken. If there is no suspicion of enlarged lymph nodes, a total thyroidectomy and central node dissection is undertaken. If enlarged nodes are detected, a block dissection of the cervical lymph nodes should be undertaken at the same time.

“Supper was served not long after returning to the ward after my

thyroidectomy. I was extremely wary about eating as my throat felt so strange, however after mixing mash potatoes with soup for my main course and finding no

problems eating that, I finished off with a hard and juicy apple for dessert!”

SSUURRGGEERRYY Total thyroidectomy + central node dissection: A small incision is made at the base of the front of the neck from which the thyroid and nearby lymph nodes can be removed. A larger incision is required if a block dissection of the cervical lymph nodes is necessary. Eating and drinking is possible almost immediately after waking up from the operation.

HHoossppiittaall SSttaayy RRiisskkss Approximately 3 – 5 days Damage to the nerves that control the vocal cords (less than 1-2%)

Unavoidable removal of or damage to the parathyroid glands resulting in a temporary drop in calcium levels in the blood, although occasionally this may be permanent. Symptoms of low blood calcium include tingling lips, fingers and toes, and eventually cramping, all of which can be corrected with medication.

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RREECCOOMMMMEENNDDEEDD AAGGEESS FFOORR PPRREE--SSYYMMPPTTOOMMAATTIICC TTHHYYRROOIIDDEECCTTOOMMYY IINN MMEENN22//FFMMTTCC DDIISSEEAASSEE GGEENNEE CCAARRRRIIEERRSS

MMuuttaatteedd FFMMTTCC CCooddoonn iinn tthhee RREETT GGeennee ((SSeeee GGeenneettiicc TTeessttiinngg EExxppllaaiinneedd))

AAggee ooff SSuurrggeerryy

609, 768, 790, 791, 804 After abnormal results on C-cell stimulation testing or between 5 to 10 years of age

MMEEDDIICCAATTIIOONN Thyroxine This is a very well established and effective replacement for the thyroid

hormones. It must be taken life-long after thyroidectomy. Tablets are taken once a day and doses are typically between 100-150mcg for adults, lower for children. Regular blood tests are required to ensure that the right dose is being prescribed. Too large a dose may cause symptoms such as rapid heartbeat, sweating, anxiety, tremor and loss of weight Too small a dose may cause symptoms such as lethargy, slow heartbeat, sensitivity to cold, and weight gain.

Calcium replacement medication (required if parathyroid glands are damaged or unavoidably removed along with the thyroid)

Alfacalcidol (brand names AlfaD, ergocalciferol) is a Vitamin D supplement in capsule form which aids absorption of calcium from the patient’s diet. Taken once a day, this is often the only life-long medication required after parathyroid loss. Calcium Carbonate (brand name, Calcichew) is a chalk-like tablet that has to be chewed or sucked. This is often used as a temporary calcium “top-up” after surgery, but is not necessarily required life-long.

If, after surgery, calcitonin levels are still raised, this may indicate that the cancer has spread (become metastatic) or has not been completely removed. Searching for metastatic disease may involve various scans and even a laparoscopy (telescopic inspection of the abdomen). Further surgery and other therapies are used to control it. If the disease is thought to be confined to the neck, then radiotherapy to the neck area may be advised. Sometimes a patient may still be cured by meticulous removal by surgery of further lymph nodes, particularly in the neck and around the chest area. MMIIBBGG TTHHEERRAAPPYY: Where surgery is no longer an option due to the extent of the disease, some specialised medical centres may use 131I-meta-iodobenzylguanidine ((131)I-mIBG), a radioactive therapy which has very few side effects, to help reduce or control the spread. However, it is only appropriate if tests suggest that this radioisotope will be taken up by the tumour. The agent is attached to a radioactive substance, and is given through a vein by slow injection. The patient remains radioactive for a few days and therefore must be nursed in a lead-lined room. The treatment may need to be repeated several times at 3 or 6 month intervals.

Treating MTC (Continued)

PPoossssiibbllee SSiiddee EEffffeeccttss ooff MMIIBBGG TThheerraappyy

Nausea, and occasionally vomiting

Children and FMTC

Deciding to Have Children

There is a 1:2 chance that a child born to a known FMTC parent will also have FMTC. If a child is known to carry the altered gene, testing and treatment programmes may be established from the outset, and conditions addressed and managed before serious symptoms develop. Ante-natal testing is available. Would-be mothers can be referred to one of the 23 UK clinical genetics centres before they become pregnant. However, since early treatment is available, antenatal testing would be a personal choice, often depending upon their own experience with the disease.

DNA Testing for Children Children of an FMTC parent with a known mutation, can be offered a genetic test to determine if they also carry the gene. This is usually offered soon after birth. You should discuss this with a genetic counsellor at your Regional Genetics Services Centre.

Treatment and Testing Recommendations For a child carrying a known MEN2 gene mutation for FMTC, total thyroidectomy to prevent the development of medullary thyroid cancer is recommended between 5 to 10 years of age, depending upon the precise mutation. The geneticist will be able to advise on this. In the hands of an experienced surgeon and team, many children cope much better with this surgery than some adults.

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DDiisseeaassee TTeesstt IInnffoorrmmaattiioonn Medullary Thyroid Cancer (MTC)

Baseline Calcitonin A simple blood test to detect calcitonin levels [NB: once drawn, the blood must be taken immediately and on ice to a chilled centrifuge in the lab]

Children and FMTC (Continued) Older Children Older children of recently diagnosed cases should be investigated straight away due to the high incidence of MTC in MEN2 gene fault carriers.

Blood Tests There are many adults who find blood tests difficult, so no parent should be surprised if their child develops an intense dislike to them as well. For small children, many hospitals use Ametop or Emla Cream (“magic cream”) covered by plasters to numb the hands and/or arms ready for the test. The cream takes up to an hour to work during which time the child may focus on the area and become distressed. In these cases, it is sometimes quicker and easier either not to use the cream at all or to use a topical anaesthetic spray instead. A phlebotomist experienced in doing children’s blood tests is a must to ensure as few repeated jabs and tests and thereby as little distress for the child as possible.

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Genetic Testing Explained Chromosomes and Genes In each cell of the body there are 23 pairs of chromosomes that contain our genes. We inherit one chromosome from each pair from each parent. This means that we inherit one copy of each gene from each of our parents, thereby giving us two copies. In most people there are two normal functioning MEN2 genes. In patients with FMTC, one of this pair has a fault. This can be inherited from either parent (inherited or familial) or can start in an individual for the first time (new mutation or sporadic). When someone with FMTC has children they can pass on either the normal gene or the faulty gene. This is entirely random, like tossing a coin. Each child therefore has a 1 in 2 or 50% chance of inheriting the faulty gene (“D” below), and is therefore predisposed to developing medullary thyroid cancer (MTC). This method of inheritance is called autosomal dominant inheritance.

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Genetic Testing Explained (Continued)

Genetic Testing It is possible in some families to have a genetic test to see whether someone has inherited the gene fault. However, the first step is to have a blood sample tested from someone with FMTC in the family. With this initial test (mutation screen), the result may not be received for a number of months, and, indeed, the gene fault is not always found. If the gene fault is found, a blood test (predictive genetic testing) may then be offered to other members of the family. The results from predictive genetic testing are received normally within several weeks. There are a number of issues surrounding predictive genetic testing particularly in relation to children and as such, all patients should be seen and counselled by a consultant clinical geneticist. If the gene fault cannot be found or if a blood sample from an affected person cannot be obtained then predictive genetic testing cannot be done. Having children tested is a very individual decision, however, if children of a known FMTC parent are tested, those unaffected can rest assured that no further investigations are required. Those who have inherited the gene can be comforted by the fact that testing and treatment patterns will determine as early as possible when intervention is required. Thanks to this early detection by DNA test, complications from advanced medullary thyroid cancer may be drastically reduced. Genetic testing and counselling is available at 23 regional genetic centres throughout the UK (www.bshg.org.uk, and see our leaflet on Genetics). A referral to a genetic centre is usually made through your GP or specialist.

In the MEN2 gene, the mutation causing FMTC can occur in one of several different areas called ccooddoonnss. Research has determined that mutations of different codons can relatively accurately predict to what extent and at what age the FMTC will manifest itself. Ultimately, this knowledge enables doctors to tailor testing and treatment programmes to the patient’s needs accordingly.

Useful Organisations

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TThhee BBrriittiisshh TThhyyrrooiidd FFoouunnddaattiioonn PO Box 97 Clifford

Wetherby West Yorkshire

LS23 6XD Tel: 0870 770 7933

www.btf-thyroid.org.uk

GGeenneettiicc IInntteerreesstt GGrroouupp ((GGIIGG)) Unit 4D, Leroy House

436 Essex Road London N1 3QP

Tel: 020 7704 3141 www.gig.org.uk

CCoonnttaacctt aa FFaammiillyy 209-211 City Road

London EC1V 1JN

Tel: 010 7608 8700 www.cafamily.org.uk

Useful Information

FFRREEEE PPRREESSCCRRIIPPTTIIOONNSS: If you are to take lifelong thyroxine, you are entitled to free prescriptions for all medicines. You should obtain a P11 leaflet from your doctor and fill in form B. You doctor will then sign it and send it on. You will then receive an exemption certificate, which you must show to your pharmacist when collecting medicines. MMEEDDIICCAALLEERRTT®®: AMEND recommends that anyone taking lifelong medications obtain and wear a MedicAlert® identification emblem. The emblem contains summarised information of your medical condition and a 24-hour Helpline number for emergency medical staff to call in order to obtain detailed information on your medical condition from the MedicAlert database. This enables emergency medical staff to give appropriate treatment in full knowledge of your underlying condition and current medications. Emblems come in a range of styles so that there is something for everyone, even children. Telephone AMEND for an order form and brochure or join online at www.medicalert.org.uk.

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About AMEND

Other AMEND Publications

AMEND was set up in 2002 by Liz Dent and her daughter Emily Fazal who both have MEN1. They were concerned that, being diagnosed with a rare condition, there was little information to be found regarding best treatment, and even fewer fellow patients with whom to be in contact to share experiences – a process that so many people find helpful. We hope that this information will go some way to making your choices easier to understand and therefore possibly easier to make. The aims of AMEND are to improve the well-being of all persons affected by MEN by providing them with information in the form of leaflets and medical journal extracts, and promoting a wider knowledge of MEN among the medical profession to assist in early and accurate diagnosis. In addition, AMEND have a number of trained Telephone Buddies who are patients and carers affected by MEN themselves. Should you wish to contact them, having someone else in a similar situation to yourself to talk to may make things easier to cope with. Membership is just £15 per annum (£10 per annum concessions; overseas £25 for 2yrs). Just call the number on the front cover to ask for a membership pack. Members receive a quarterly newsletter containing interesting and relevant news and other articles, as well as an “Ask the Doctor” section, invitation to AMEND’s annual assembly, automatic updates on any recent medical and surgical advances and the opportunity to become a Telephone Buddy.

Comments

AMEND continually strives to make it’s information as accurate and up-to-date as possible. As such, should you have any comments regarding this publication, please send them to Mrs Jo Grey, AMEND MEN2 Representative, 31 Pennington Place, Southborough, Kent, TN4 0AQ, or by email to jo.grey@amend.org.uk. We welcome comments from both patients and medical professionals.

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I could not have written this patient information book without the kind help and support of the AMEND medical advisory team listed below to whom I extend my grateful thanks:

Professor Rajesh Thakker, University of Oxford, Oxford Centre for Diabetes, Endocrinology & Metabolism;

Dr Caroline Brain, Consultant Paediatric Endocrinologist, The Middlesex Hospital/GOSH, London;

Professor John Connell, Department of Medicine and Therapeutics, Western Infirmary, Glasgow;

Professor Ashley Grossman, Department of Endocrinology, St Bartholomew’s Hospital, London; Dr Fiona Lalloo, Consultant Clinical Geneticist, St Mary’s Hospital, Manchester; Mr David Scott-Coombes, Department of Surgery, University Hospital of Wales, Cardiff; Professor Dorothy Trump, Department of Medical Genetics, St Mary’s Hospital, Manchester; Professor Tony Weetman, University of Sheffield Clinical Sciences Centre, Sheffield.

Special thanks must also go to the following:

Max Chater, Simon Friend and Steve Hall, 2004/05 students from West Kent College in Tonbridge, Kent, for the superb illustrations;

My fellow patients whose personal experiences and opinions were so helpful; My family for their support, encouragement and forbearance!

Jo Grey AMEND

Maria Luisa Brandi, Robert F Gagel, Alberto Angeli et al 2001, Consensus: Guidelines for Diagnosis and Therapy of MEN Type 1 and Type 2, The Journal of Clinical Endocrinology & Metabolism 86(12): 5658-5671

Rajesh Thakker 1998, Editorial: Multiple Endocrine Neoplasia – Syndromes of the Twentieth Century, Journal of Clinical Endocrinology and Metabolism, Vol 83, No 8

CJM Lips et al, Introduction to Multiple Endocrine Neoplasia Syndromes, Topical Endocrinology, Issue 18, July 2001

Andreas Weinhausel, Monika Fink et al, Clinical Management of Patients with MEN Syndromes, Topical Endocrinology, Issue 18, July 2001

LB Johnston et al 2000, Screening children at risk of developing inherited endocrine neoplasia syndromes, Clinical Endocrinology (2000) 52, 127-136

M Schlumberger, F Pacini 1997, Medullary Thyroid Carcinoma, Tumeurs de la Thyroïde, Éditions Nucléon, 1997

The British Medical Association, New Guide to Medicines and Drugs, Revised Edition, Dorling Kindersley 2001

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© Association for Multiple Endocrine Neoplasia Disorders (AMEND), May 2005