Summary

Multiple Endocrine Neoplasia Type 2 (MEN 2) is a rare autosomal dominant hereditary cancer syndrome caused by germline activating mutations in the RET proto-oncogene. It is the textbook example of Genotype-Phenotype Correlation: The specific codon mutation predicts exactly when the cancer will start, how aggressive it will be, and which organs will be affected.

The syndrome is divided into three subtypes:

1. MEN 2A (95%): Medullary Thyroid Cancer (MTC), Phaeochromocytoma, Parathyroid Hyperplasia.
2. MEN 2B (5%): MTC (Very Aggressive, infancy), Phaeochromocytoma, Mucosal Neuromas, Marfanoid Habitus. No Parathyroid disease.
3. FMTC (Familial Medullary Thyroid Cancer): MTC only. (Now often considered a variant of MEN 2A).

The "Killers"

1. Medullary Thyroid Cancer (MTC):
   • Found in almost 100% of patients.
   • Arises from Parafollicular C-Cells (neuroendocrine cells).
   • Secretes Calcitonin (and CEA).
   • The Problem: It metastasizes early (lymph nodes -> liver/bone) and chemotherapy/radioiodine DO NOT WORK. Surgery is the only cure.
2. Phaeochromocytoma:
   • Found in 50% of patients.
   • Usually bilateral (unlike sporadic phaeos).
   • The Problem: Sudden hypertensive crisis during surgery if not blocked. "The Anaesthetist's Nightmare".

Key Facts Table

The RET Proto-oncogene: A Molecular Masterpiece

The RET (Rearranged during Transfection) proto-oncogene is located on the long arm of Chromosome 10 (10q11.2). It encodes a single-pass transmembrane receptor tyrosine kinase that is critical for the development of:

1. The Neural Crest: Progenitors of the Enteric Nervous System (ENS) and Autonomic Nervous System.
2. The Urogenital System: Critical for kidney budding.

The Normal "Brake and Gas" System

In a healthy cell, growth is tightly regulated.

• The Brake: The RET receptor sits on the cell membrane in an inactive monomeric state. It does nothing.
• The Gas: When the ligand GDNF (Glial Cell Line-Derived Neurotrophic Factor) binds to a co-receptor (GFRalpha1), this complex recruits two RET monomers.
• Activation: The two RET monomers come together (Dimerization). This proximity allows their intracellular Tyrosine Kinase domains to phosphorylate each other (Autophosphorylation).
• Signal: This spark sets off a cascade of downstream signals (MAPK, PI3K/AKT, STAT3) that tell the cell to survive, migrate, and divide. Once the job is done, the receptor is internalized and degraded. The car stops.

The MEN 2 Mutation: "The Brick on the Pedal"

In MEN 2, the DNA code has a single spelling mistake (point mutation) that breaks this control system. The nature of the break determines the disease (Genotype-Phenotype Correlation).

1. MEN 2A: The "Sticky" Receptor (Exon 10 & 11)

• The Defect: Mutations affect the Extracellular Cysteine-Rich Domain (Codons 609, 611, 618, 620, 630, 634).
• The Mechanism: Cysteine amino acids are unique because they form strong "disulfide bridges". Normally, these bridges hold the receptor's shape.
• The Glitch: The mutation removes a cysteine. This leaves an "unpaired" cysteine looking for a partner. Two mutant RET receptors find each other and form a covalent disulfide bond between them.
• The Result: The receptors are permanently stuck together (Dimerized) even without any GDNF ligand. They fire continuously, but at a moderate level.
• Clinical Consequence: MTC develops in childhood/adulthood. Phaeochromocytomas occur but are manageable.

2. MEN 2B: The "Broken Engine" (Exon 16)

• The Defect: The mutation is inside the cell, in the Tyrosine Kinase Catalytic Domain. 95% are M918T (Methionine to Threonine at codon 918).
• The Mechanism: This mutation changes the physical shape of the "engine room" (the ATP binding pocket).
• The Glitch: The kinase no longer needs to dimerize to fire. It is inherently active in its monomeric state. Furthermore, it changes the specificity of the kinase, allowing it to phosphorylate targets it normally wouldn't (like STAT3).
• The Result: Explosive, high-intensity signaling. It drives rapid cell division and prevents apoptosis (cell death).
• Clinical Consequence: MTC starts in infancy and metastasizes immediately. The nerves in the lips, tongue, and gut grow wildly (neuromas). The bones grow abnormally (Marfanoid habitus).

3. Hirschsprung's Disease: "The Cut Cable"

• Interestingly, different mutations in RET can impede its function.
• Loss of Function: If RET cannot signal, the Neural Crest cells fail to migrate to the colon during embryology.
• Result: A colon without nerves (Aganglionic Megacolon).
• The "Janus" Mutations: Some Exon 10 mutations (C609, C618, C620) make the receptor "sticky" (causing cancer) but also prevent it from reaching the cell surface efficiently (causing Hirschsprung's). These patients have BOTH.

Image: RET Signaling Cascade

Figure 1: The difference between ligand-dependent activation (Normal) and constitutive activation (MEN 2).

The American Thyroid Association (ATA) has revolutionized the management of MEN 2 by creating a "Risk Bible". We no longer treat based on what we see (Phenotype); we treat based on what is written in the DNA (Genotype).

Review of the ATA Risk Levels (2015 Update)

The "Grey Zone": Variants of Uncertain Significance (VUS)

With widespread genetic testing, we often find RET variants that are not in the guidelines. Use the ACMG Criteria:

1. Is it in a known hotspot (Exon 10, 11, 13, 14, 15, 16)?
2. Does it track with disease in the family?
3. Does in silico modeling predict protein damage? Action: Treat as MOD risk but monitor Calcitonin fiercely.

The presentation involves multiple systems.

1. The Thyroid (First and Foremost)

• The Silent Phase: For gene carriers, there are usually NO symptoms. The thyroid feels normal. This is why biochemical screening is vital.
• The Nodule: A firm, painless, solitary nodule is the first sign of established cancer.
• Advanced Signs:
  • Lymphadenopathy: Hard, fixed nodes in the lateral neck (Levels II, III, IV).
  • Dysphagia: Difficulty swallowing as the tumour invades the oesophagus.
  • Stridor: Noisy breathing from tracheal compression.
  • Hoarseness: Invasion of the Recurrent Laryngeal Nerve (RLN). This is a menacing sign of extrathyroidal extension (T4 disease).

2. The Adrenals (Phaeochromocytoma)

In MEN 2, phaeochromocytomas are:

• Bilateral (50-70%).
• Benign (Malignancy is rare in MEN 2, unlike SDH mutations).
• Secretory (Produce Adrenaline and Noradrenaline).

Symptoms ("The Great Mimic"):

• Paroxysmal Attacks: Sudden onset of specific symptoms lasting 15-60 minutes.
  • Headache: Throbbing, bilateral.
  • Sweating: Profuse, drenching upper body sweat.
  • Palpitations: Forceful pounding (Tachycardia).
• Triggers: Exercise, bending over, surgery, tyramine-rich foods, beta-blockers.
• The "Death Spell": Some patients present with "Flash Pulmonary Oedema" or Multisystem Crisis (Takotsubo Cardiomyopathy) due to catecholamine storm.

3. The Parathyroids (Hypercalcaemia)

Only in MEN 2A.

• Mechanism: Multi-gland hyperplasia (all 4 glands grow big).
• Presentation:
  • Renal: Kidney stones (Calcium oxalate). Nephrocalcinosis.
  • Bone: Osteitis Fibrosa Cystica (Brown tumours) - rare now. Osteoporosis.
  • Gut: Constipation, Pancreatitis, Peptic Ulcers.
  • Brain: "Moans and Groans" - Depression, Fatigue, Brain Fog.

4. Cutaneous & Physical Features (MEN 2B Only)

MEN 2B is a distinct physical syndrome. You can diagnose it from the end of the bed.

• Marfanoid Habitus:
  • Tall stature, thin body mass.
  • Arachnodactyly (Video-game fingers).
  • Pectus excavatum (Sunken chest).
  • Scoliosis.
  • High-arched palate.
  • Differentiation from Marfan's: No lens dislocation, No aortic root dilation.
• Mucosal Neuromas:
  • Painless, glistening, bump-like nodules on the anterior tongue, lips, and inside cheeks.
  • "Blubbery Lips": The lips look swollen and bumpy.
• Ocular Findings:
  • Thickened Corneal Nerves: Visible on slit-lamp.
  • Everted upper eyelids.
• Gastrointestinal:
  • Intestinal Ganglioneuromatosis: Neuromas throughout the gut wall.
  • Causes severe constipation, megacolon, and distension.
  • Often misdiagnosed as Hirschsprung's in infancy.

5. Cutaneous Lichen Amyloidosis (MEN 2A Variant)

• A specific skin rash seen in some MEN 2A families (Codon 634).
• Appearance: Itchy, scaly, hyperpigmented plaque on the upper back (interscapular area).
• Cause: Not clearly understood, possibly scratching induced by neurological hypersensitivity.

Prophylactic Thyroidectomy: The Preventative Strike

The hallmark of MEN 2 management is removing the thyroid before the cancer becomes dangerous.

• The Principle: C-Cell Hyperplasia precedes Medullary Carcinoma. If we remove the gland at the hyperplasia stage, the cure rate is 100%.
• The Procedure: Total Thyroidectomy. Hemithyroidectomy is CONTRAINDICATED because the genetic defect affects every C-cell in the gland. Recurrence in the remnant is guaranteed.

Timing by Genotype (Crucial)

1. HST (MEN 2B): Operate in the First Year
   • These babies often have metastases at diagnosis. Use extreme urgency.
   • Requires expert paediatric anaesthesia and surgery.
   • Central node dissection is usually required because nodes are often positive.
2. HIGH (Classic MEN 2A): Operate by Age 5
   • This balances the risk of cancer progression against the risk of surgical complications (hypoparathyroidism) in very small children.
   • If family compliance is perfect and Calcitonin is undetectable, some surgeons wait until age 5-7 to allow the parathyroids to grow larger (easier to save).
3. MODERATE (FMTC): Personalized Timing
   • Some patients carry the gene but have normal Calcitonin for decades.
   • Option A: Operate in childhood (eliminate the problem/anxiety).
   • Option B: Surveillance. Measure Calcitonin every 6 months. Operate only if it rises above normal range. This avoids lifelong Thyroxine if not strictly necessary yet.

Therapeutic Thyroidectomy (Established Cancer)

If a lump or positive nodes are present:

1. Total Thyroidectomy.
2. Central Neck Dissection (Level VI): Mandatory. This compartment (Hyoid to Innominate artery, Carotid to Carotid) contains the paratracheal and pretracheal nodes.
   • Technique: En-bloc resection.
   • Risk: High risk of transient hypocalcaemia (30-50%) and RLN injury.
3. Lateral Neck Dissection (Levels II-V):
   • Indication: Only if lateral nodes are proven on US/Biopsy, OR if Calcitonin >20 pg/mL.
   • Technique: Modified Radical Neck Dissection (sparing IJV, SCM, and Accessory Nerve).

Post-Operative Management

• Levothyroxine (T4): Replacement dose (approx 1.6 mcg/kg).
• Target TSH: 0.5 - 2.0 mU/L (Normal range).
  • Note: Unlike Differentiated Thyroid Cancer (Papillary/Follicular), TSH suppression <0.1 is NOT required. C-Cells do not have TSH receptors. Suppressing TSH causes osteoporosis/AF without slowing the cancer.
• Calcium/Vitamin D: Most children need supplements for 2-6 weeks post-op due to "stunned" parathyroids.

The Golden Rule: Start Alpha Blockade BEFORE Beta Blockade. (A before B).

Pre-Operative Preparation (Roizen Criteria)

Before touching a phaeochromocytoma, the patient must be "Optimized". Surgery is cancelled if these criteria are not met:

1. Blood Pressure: <130/80 sitting, and >90 systolic standing (Postural Drop).
2. Pulse: 60-70 sitting, 70-80 standing.
3. ST Segments: No ischaemic changes on ECG.
4. Duration: Minimum 10-14 days of blockade.

The Drug Protocol

1. Alpha Blockade (Phenoxybenzamine):
   • Non-competitive, irreversible alpha-antagonist.
   • Start 10mg BD, titrate up.
   • Mechanism: Vasodilates arterioles. Allows the constricted plasma volume to re-expand.
   • Side Effects: Stuffy nose, postural dizziness (warn the patient!).
2. Beta Blockade (Propranolol/Bisoprolol):
   • Start after 3-4 days of alpha blockade.
   • Mechanism: Controls the tachycardia caused by the alpha-blocker reflex.
   • Danger: If given alone, it blocks Beta-2 (vasodilator) receptors, leaving Alpha-1 (vasoconstrictor) receptors unopposed. BP skyrockets -> Stroke.

Surgical Strategy: "The Cortical Sparing" Approach

In sporadic Phaeo, we remove the whole adrenal gland. In MEN 2, we differ.

• The Problem: MEN 2 affects both adrenals. Removing both means the patient has Zero Cortisol and Zero Aldosterone. They become dependent on Fludrocortisone and Hydrocortisone for life.
• Addisonian Crisis: A leading cause of death in MEN 2 patients is not the cancer, but an adrenal crisis (vomiting -> cannot absorb tablets -> shock -> death).
• The Solution: Cortical-Sparing Adrenalectomy.
  • The surgeon carefully dissects the medullary tumour away from the yellow cortical rim.
  • Leaving just 15-30% of one adrenal cortex is enough to maintain cortisol independence.
  • Risk: 10-20% recurrence rate in the remnant. But this buys 10-20 years of steroid independence.

Surgical Approaches

1. Laparoscopic Transperitoneal: Standard. Good for large tumours (>6cm).
2. Posterior Retroperitoneoscopic (PRA): The modern gold standard.
   • Patient lies prone (face down).
   • Direct access to adrenal without touching the bowel/liver/spleen.
   • Less pain, faster recovery, no scars on tummy.

The Dilemma

Hyperparathyroidism (HPT) in MEN 2 is usually multi-glandular hyperplasia. If you leave a gland, it will grow. If you take them all, the patient has permanent hypocalcaemia.

Surgical Options

1. Subtotal Parathyroidectomy (3.5 Gland Resection): Remove 3 glands entirely. Leave a well-vascularized nugget of the 4th gland (approx 50mg, size of a pea).
2. Total Parathyroidectomy with Autotransplantation:
   • Remove all 4 glands.
   • Mince one gland into 1mm fragments.
   • Implant 10-20 fragments into a pouch in the Brachioradialis muscle (Forearm) or Sternocleidomastoid.
   • Logic: If HPT recurs, you can operate on the arm under local anaesthetic. Re-exploring a scarred central neck is hazardous to the RLN.

Calcimimetics (Cinacalcet)

• Used for patients unfit for surgery or with recurrent disease.
• Tricks the Calcium-Sensing Receptor (CaSR) into thinking calcium is high, lowering PTH secretion.

When surgery fails (distant mets), chemo is useless. We use targeted molecular therapy.

Non-Selective TKIs

1. Vandetanib: Targets RET, VEGFR, EGFR. Approved for symptomatic MTC.
   • Side Effects: Diarrhea, Rash, QT prolongation.
2. Cabozantinib: Targets RET, VEGFR2, MET.
   • Side Effects: Hand-Foot syndrome, hypertension.

Selective RET Inhibitors (The Game Changers)

1. Selpercatinib (LOXO-292).
2. Pralsetinib (BLU-667).

• Mechanism: Specifically target the mutant RET pocket.
• Efficacy: Huge response rates (>60-70%). Less side effects. Even works on Brain Mets.

• The Paradox: RET Loss-of-Function mutations cause Hirschsprung's (No nerves in bowel). RET Gain-of-Function causes MEN 2 (Cancer).
• Crossover: Some specific Exon 10 mutations (C609, C611, C618, C620) can cause BOTH MEN 2A and Hirschsprung's in the same patient. These are "Janus" mutations.

• Screening: Ideally treat phaeo/thyroid before conception.
• Phaeo in Pregnancy: High maternal/fetal mortality. Alpha block. Operate in 2nd trimester if needed. C-Section preferred.
• MTC: Calcitonin naturally rises slightly in pregnancy. Monitor. Avoid X-Ray/CT.

• 1961: John Sipple describes the association between thyroid cancer and phaeochromocytoma.
• 1993: Donis-Keller identifies RET as the causative gene. This revolutionized the field, moving from "wait for cancer" to "prevent cancer".

1. The Missed Phaeo: Operating on a neck lump without checking metanephrines. Patient dies on table. Negligence.
2. The Failure to Screen: Diagnosing a young person with MTC but failing to test their children. Child presents 5 years later with incurable metastatic disease.
3. The Wrong Operation: Doing a "lumpectomy" for MTC. It needs Total Thyroidectomy + Central Node clearance.

To understand MEN 2A, we must follow a patient not for days, but for decades.

The Patient: "Sarah", Genotype C634 (High Risk)

• Age 0 (Diagnosis):
  • Sarah's father is diagnosed with MTC at age 30. Genetic testing confirms he has the C634 mutation.
  • Sarah is tested as a baby. She is positive.
  • Advice: Prophylactic Thyroidectomy planned for age 4.
• Age 4 (The Thyroidectomy):
  • Pre-op Calcitonin: Normal (<2 pg/mL).
  • US Neck: Normal.
  • Surgery: Total Thyroidectomy. No central neck dissection needed (Calcitonin normal). Parathyroids preserved.
  • Histology: C-Cell Hyperplasia only. No cancer.
  • Result: Cured of MTC for life. Started on Levothyroxine 50mcg.
• Age 15 (The First Scare):
  • Annual screening reveals elevated Plasma Metanephrines.
  • BP: 110/70 (Normal).
  • MRI Adrenals: 2cm mass in Right Adrenal.
  • Diagnosis: Right Phaeochromocytoma.
  • Management: Phenoxybenzamine blockade x 2 weeks. Laparoscopic Cortical-Sparing Adrenalectomy.
  • Outcome: Steroid independent.
• Age 28 (Pregnancy):
  • Sarah wants a baby.
  • PGD: She chooses Pre-implantation Genetic Diagnosis to ensure the baby does not carry C634.
  • Adrenal Check: Essential before conception. Metanephrines normal.
  • Outcome: Healthy boy delivered (MEN 2 negative).
• Age 45 (The Parathyroids):
  • Routine bloods show Calcium 2.85 mmol/L (High), PTH 15 pmol/L (High).
  • Diagnosis: Primary HPT.
  • Surgery: 3.5 Gland Resection.
  • Outcome: Normocalcaemia.

Reflection

Sarah has had 3 major surgeries but leads a normal life. Without the genetic test at Age 0, she would likely have presented with metastatic MTC at age 30 (like her father) and died by 40. This is the triumph of genomic medicine.

In specialist centres, the Endocrine Nurse Specialist is the linchpin of care.

1. The Coordinator

• MEN 2 patients need: Thyroid surgeon, Endocrine Physician, Geneticist, Paediatrician, Oncologist.
• The Nurse ensures these appointments happen on the same day ("One-Stop Clinic") to reduce burden on families.

2. The "Calcitonin Tracker"

• Maintains a database of all gene carriers.
• Ensures annual calcitonin/metanephrine checks are actually done.
• Red Flagging: If a patient misses an appointment, the Nurse hunts them down. In MEN 2, "Lost to follow-up" = "Death by neglect".

3. Education & Support

• Pre-Genetic Testing: Explaining the implications of a positive result (insurance, career, guilt).
• Pre-Thyroidectomy: Teaching parents about Levothyroxine administration (crushing tablets in milk) and hypocalcaemia signs (tingling fingers).
• Pre-Phaeochromocytoma: Explaining the side effects of Alpha Blockade (" You will get a stuffy nose and feel dizzy when you stand up - this means the drug is working").

When surgery is no longer an option (unresectable metastases), we turn to systemic therapy.

Vandetanib (Caprelsa)

• Class: Multi-kinase inhibitor (RET, EGFR, VEGFR).
• Indication: Symptomatic, aggressive MTC.
• Dose: 300mg PO daily.
• Pharmacology: Long half-life (19 days).
• Critical Toxicity: QT Prolongation.
  • Vandetanib can cause Torsades de Pointes / Sudden Cardiac Death.
  • Protocol: ECG at baseline, week 2, 4, 8, 12, and every 3 months.
  • Contraindication: Long QT syndrome, hypokalaemia, bradycardia.
  • Because of this risk, it is prescribed under a restricted distribution program (REMS).
• Other Side Effects:
  • Diarrhea (50%): Manage with Loperamide.
  • Rash (Acneiform): Topical clindamycin/steroids.
  • Photosensitivity: Strict sun avoidance.

Cabozantinib (Cometriq)

• Class: Multi-kinase inhibitor (RET, MET, VEGFR2).
• Indication: Progressive, metastatic MTC.
• Dose: 140mg PO daily.
• Pharmacology: Potent VEGFR2 inhibition leads to vascular side effects.
• Side Effects:
  • Hand-Foot Skin Reaction (Palmar-Plantar Erythrodysesthesia): Red, painful blistering of hands/feet. Dose limiting.
  • Fistula Formulation: GI perforation/fistula (Rare but fatal).
  • Hypertension/Bleeding: Vascular effects.

Selpercatinib (Retevmo) - The New Standard

• Class: Selective RET Inhibitor.
• Mechanism: Designed to fit the ATP pocket of MUTANT RET specifically. Spares EGFR/VEGFR.
• Advantage: Much "cleaner" side effect profile (Less rash/diarrhea/QT issues).
• Efficacy:
  • LIBRETTO-001 Trial: ORR 69% in pre-treated patients. 73% in naive patients.
  • CNS Penetration: Crosses Blood Brain Barrier (Treats Brain Mets!).
• Side Effects:
  • Hypertension (30%).
  • Elevated LFTs (AST/ALT).
  • Hyponatraemia.

Q: Did I inherit this? A: Usually yes (Inherited). But 50% of MEN 2B cases are "de novo" (new mutations in the sperm/egg) with no family history.

Q: Can I have children? A: Yes. There is a 50% chance of passing it on. Pre-implantation Genetic Diagnosis (PGD) (IVF with embryo selection) can ensure a baby does not carry the gene.

Q: Is MTC curable? A: If caught early (Stage I/II), Yes (Surgery). If distant metastases (Stage IV), no, but it is slow growing and treatable for many years.

Q: What foods should I avoid with Phaeo? A: Foods high in Tyramine (cheese, wine) can theoretically trigger attacks, but modern advice focuses on Alpha Blockade medication.

• Proto-oncogene: A normal gene that, when mutated, becomes an oncogene (cancer driver).
• Autosomal Dominant: One copy of the faulty gene is enough to cause disease. 50% Risk to offspring.
• Marfanoid: Looking like Marfan syndrome (tall, lanky) but genetically different.
• Ganglioneuromatosis: Overgrowth of nerve cells in the gut.
• Metanephrines: Breakdown products of adrenaline/noradrenaline. Tested in urine/blood.
• Calcitonin: Hormone from C-cells. Lowers blood calcium (minor role) but serves as excellent Tumour Marker.

For Educational Review Only - Not a surgical manual.

Patient: 5-year-old child (MEN 2A, Codon 634). Indication: Prophylactic Thyroidectomy to prevent MTC. Incision: Collar incision in skin crease (Kocher). Flaps: Raised sub-platysmal. Mobilization: Strap muscles separated. Thyroid isthmus divided. Dissection:

1. Lateral Dissection: Gland mobilized medially. Middle thyroid vein ligated.
2. Recurrent Laryngeal Nerve (RLN): Identified at thoracic inlet. Tracked to entry point at Cricothyroid joint. Preserved.
3. Parathyroids: Identified (x4). Vascularity preserved if possible. If devascularized -> Autotransplant.
4. Central Compartment (Level VI): All fibro-fatty tissue between Carotids, from Hyoid to Innominate Artery, removed en bloc. (This contains the paratracheal nodes - the first site of metastasis). Closure: Layered. Drain placed. Post-Op: Calcium monitoring (hypocalcaemia risk).

The diagnosis of Phaeochromocytoma is often made when the patient crashes on the table.

Trigger: Induction of anaesthesia, abdominal palpation, or tumour handling squeezes adrenaline into blood. Signs: sudden BP surge (>220/120), Tachycardia (>140), Arrhythmia. Immediate Action:

1. STOP SURGERY. Inform surgeon.
2. Deepen Anaesthesia: Increase Sevoflurane/Propofol (reduce sympathetic outflow).
3. Drugs:
   • Phentolamine (IV Alpha Blocker): Bolus 2-5mg. Repeat as needed. This is the antidote.
   • Magnesium Sulphate: Stabilizes myocardium, vasodilates.
   • Labetalol: ONLY after alpha blockade is working. (Mixed alpha/beta). Golden Rule: Never give pure Beta-blockers (Metoprolol/Bisoprolol) first. It causes "Unopposed Alpha" (Massive vasoconstriction + Cardiac failure).

A reference for the specific mutations.

"How do I tell my family?"

1. The Letter: We will provide a "To Whom It May Concern" letter for your relatives.
2. The Rule: "First Degree Relatives" (Parents, Siblings, Children) are at 50% risk.
3. The Test: It is a simple blood test. Results take 4-8 weeks.
4. Children: We usually test children by age 3-5 (for MEN 2A) or immediately (for MEN 2B).
5. Insurance: In the UK, genetic results for preventative surgery (like this) usually do not affect life insurance adversely (Check the ABIM Code).
6. Guilt: "You did not 'give' this to your child. Genes are random. Knowing the gene is a gift—it allows us to cure them before they get sick."

For Specialist Reference Only

Standard Script for "breaking bad news" (Positive gene test)

1. The Setting: Private room, specialist nurse present.
2. The Opening: "The results have come back from the lab. As we discussed, we were looking for a spelling mistake in the RET gene. The test confirms that you do carry this alteration."
3. The Immediate Reassurance: "This does not mean you have cancer right now. It means you have a higher risk. But because we know this now, we can prevent it."
4. The Plan: "We will check your thyroid hormone levels and calcitonin today. Ideally, we recommend removing the thyroid gland preventatively."

Family Planning Options Detail

• Prenatal Testing:
  • Testing the fetus at 11 weeks (CVS) or 15 weeks (Amnio).
  • Dilemma: Would you terminate a pregnancy for a treatable condition? Most parents say no.
• PGD (Pre-implantation Genetic Diagnosis):
  • Creates embryos via IVF.
  • Biopsy day 5 blastocyst.
  • Only implant "RET-Negative" embryos.
  • Success Rate: approx 30-40% per cycle. Costly (£10k-£15k if private).

While diet cannot fix genes, it manages the consequences (Post-Thyroidectomy, Post-Adrenalectomy).

1. Post-Thyroidectomy Weight Management

• Metabolic Rate: Without a thyroid, the BMR drops until T4 is optimized.
• Weight Gain: Patients often gain 2-5kg in the first year.
• Strategy:
  • Calorie deficit of 200kcal/day.
  • High protein diet to preserve muscle mass.
  • Levothyroxine Absorption: Take on empty stomach with water. No coffee/calcium for 4 hours. (Coffee reduces absorption by 30%).

2. Post-Adrenalectomy Salt Cravings

• If bilateral adrenalectomy is performed (Addisonian state):
• Salt Wasting: Without aldosterone, the kidneys dump sodium.
• The Craving: Patients crave salty foods (crisps, soy sauce).
• Advice: Indulge the craving. They need the salt to maintain blood pressure.
• Hydration: Must drink 2-3L water daily. Dehydration = Crisis.

3. Alcohol & Phaeochromocytoma

• Tyramine: Found in aged cheese, red wine, craft beers.
• Mechanism: Tyramine displaces noradrenaline from storage vesicles.
• Risk: Can trigger a hypertensive crisis in unoperated patients.
• Advice: Absolute abstinence from red wine/cheese boards until tumor is removed.

Case Study: Doe vs Hospital Trust (2018)

• Scenario: 6-year-old child diagnosed with MEN 2A.
• Error: Surgeon performed total thyroidectomy but did NOT check plasma metanephrines pre-op.
• Event: Child had undiagnosed phaeochromocytoma. Induction of anaesthesia caused massive hypertensive crisis (BP 240/140). Child suffered stroke and permanent brain injury.
• Judgment: Finding for the claimant.
• Legal Principle: "Failure to exclude phaeochromocytoma in a known MEN 2 patient constitutes a breach of basic duty of care."
• Impact: Mandatory "Phaeo Checklist" introduced in all endocrine surgery centers.

Case Study: Smith vs GP (2015)

• Scenario: 35-year-old man with "anxiety attacks" and "palpitations".
• Error: GP prescribed Beta-Blockers (Propranolol) for anxiety.
• Event: Patient had undiagnosed Phaeo. Beta-blockade caused "Unopposed Alpha" effect. BP spiked -> Myocardial Infarction.
• Judgment: Settlement reached.
• Lesson: "Never give beta-blockers for palpitations without checking BP and considering secondary causes."

1. Gene Therapy (CRISPR/Cas9)

• Concept: Use a viral vector to deliver CRISPR machinery to thyroid C-cells.
• Mechanism: "Cut out" the mutant RET exon and paste in the wild-type sequence.
• Status: Pre-clinical (Mouse models).
• Challenge: Delivery. Getting the virus to hit 100% of C-cells is impossible. If you miss 1%, cancer still grows.

2. Peptide Receptor Radionuclide Therapy (PRRT)

• Concept: "Magic Bullet".
• Mechanism: Attach a radioactive isotope (Lutetium-177) to a molecule that binds to MTC cells (e.g., CCK-2 receptors).
• Status: Phase II trials.
• Hope: Could cure metastatic disease that is resistant to TKIs.

3. Liquid Biopsy

• Concept: Detecting "Circulating Tumour DNA" (ctDNA) in blood.
• Use: More sensitive than Calcitonin? Detecting specific resistance mutations (e.g., detecting if a tumour has acquired a V804M mutation to escape Vandetanib).

Q1: What is the specific codon associated with MEN 2B? A: Codon 918 (M918T) in Exon 16.

Q2: What is the rule for Beta-blockers in Phaeo? A: "Alpha before Beta". Never Beta first.

Q3: Which Calcium channel blocker is used for hypertension in Phaeo? A: Amlodipine or Nifedipine (add-on to Alpha blockers).

Q4: What is the half-life of Calcitonin? A: Short (approx 45 minutes). This makes it a great real-time marker.

Q5: What is the significance of CEA in MTC? A: CEA indicates dedifferentiation. High CEA with normal/low Calcitonin ("Flip Phenotype") means the tumour has become aggressive and lost its ability to make hormones. Poor prognosis.

Q6: Can you use Radioiodine (I-131) for MTC? A: NO. MTC comes from C-cells, not Follicular cells. They do not have the Sodium-Iodide Symporter (NIS). It is useless and exposes the patient to radiation for nothing.

Q7: What syndrome mimics MEN 2B? A: Multiple Mucosal Neuroma Syndrome (pure phenotype without RET mutation) - very rare. Or extreme Marfan's.

Q8: Why do we screen for HPT in MEN 2A but not MEN 2B? A: HPT does not occur in MEN 2B. It is a feature of the cysteine-rich domain mutations (MEN 2A), not the tyrosine kinase domain mutations (MEN 2B).

Q9: What is the youngest age for thyroidectomy in MEN 2B? A: As soon as safe. Cases of metastasis have been seen at 2 months old. Ideally within first 6 months.

Q10: What is the inheritance pattern? A: Autosomal Dominant with 100% penetrance (for MTC).

"I remember looking at my baby son, knowing he had the gene. I felt like I had given him a curse. But the surgeon told me: 'You didn't give him a curse, you gave him a map. We know the road ahead, and we can remove the obstacles before he even gets there.' That changed everything for me." - Maria, MEN 2A Patient

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• A - Autosomal Dominant: The inheritance pattern where only one mutated copy of the gene is needed to cause the disease. This means there is a 50% chance of passing it to each child.
• B - Bilateral: In MEN 2, phaeochromocytomas usually affect both adrenal glands (bilateral), whereas in sporadic cases they are usually unilateral.
• C - Calcitonin: A hormone produced by the parafollicular C-cells of the thyroid. In healthy people, its role is minor (lowering blood calcium). In MEN 2, it is the crucial tumour marker for Medullary Thyroid Cancer. Levels correlate directly with tumour mass.
• D - Doubling Time: The time it takes for the calcitonin level to double. This is the single most important prognostic factor in recurrent MTC. A doubling time of <6 months implies very aggressive disease and poor survival.
• E - Exon: The coding region of a gene. In RET, mutations in Exon 10 and 11 (Extracellular) cause MEN 2A. Mutations in Exon 16 (Intracellular) cause MEN 2B. This location predicts severity.
• F - FMTC: Familial Medullary Thyroid Cancer. A historical term for families who only get thyroid cancer and never get phaeochromocytoma. Now considered a mild variant of MEN 2A.
• G - Germline: A mutation present in every cell of the body (including sperm/egg), meaning it can be passed on. Contrast with 'Somatic' mutations which only exist in the tumour.
• H - Hirschsprung's Disease: A congenital absence of nerves in the colon causing bowel obstruction. It is caused by 'Loss of Function' RET mutations. It can coexist with MEN 2A in 'Janus' mutations (Codon 609/618/620).
• I - Iatrogenic: Harm caused by medical treatment. In MEN 2, the biggest iatrogenic risks are hypoparathyroidism (from aggressive surgery) and Addisonian crisis (from bilateral adrenalectomy).
• J - Janus Mutation: A mutation that has two opposing effects. Named after the two-faced Roman god. For example, C618 enhances signalling (causing cancer) but impairs transport to the cell surface (causing Hirschsprung's).
• K - Kinase: An enzyme that transfers phosphate groups. RET is a Tyrosine Kinase. The mutation makes this enzyme 'hyperactive', driving cell growth.
• L - Loperamide: A key drug for managing the secretory diarrhea of metastatic MTC. High doses are often needed.
• M - Metanephrines: The breakdown products of adrenaline and noradrenaline. They are measured in plasma or urine to screen for phaeochromocytoma. They are more stable and sensitive than measuring adrenaline itself.
• N - Neuroma: A benign growth of nerve tissue. Mucosal neuromas on the lips and tongue are the hallmark of MEN 2B. They are often the first sign of the disease in a baby.
• O - Oncogene: A gene that has the potential to cause cancer. RET is a proto-oncogene, meaning it is a good gene that turns bad when mutated.
• P - Penetrance: The likelihood that a person with the gene will get the disease. In MEN 2, the penetrance for MTC is virtually 100%. The penetrance for Phaeo is approx 50%.
• Q - Quality of Life: A major focus of modern care. Balancing the 'cure' (surgery) with the side effects (lifelong hormone replacement, scars, anxiety).
• R - RET: "REarranged during Transfection". The gene responsible for MEN 2. Located on Chromosome 10.
• S - Sipple Syndrome: The original name for MEN 2A, named after John Sipple who described the association in 1961.
• T - Tyrosine Kinase Inhibitor (TKI): A class of drugs that blocks the ATP binding site of the RET protein, shutting down the signal. Examples: Selpercatinib, Vandetanib.
• U - Unilateral: Affecting one side. Sporadic phaeochromocytomas are usually unilateral.
• V - VUS: Variant of Uncertain Significance. A genetic change where we don't know if it causes disease or not. A nightmare for clinicians.
• W - Wild-Type: The normal, non-mutated version of a gene.
• X - X-Ray: Not useful for MTC diagnosis, but used to look for lung metastases.
• Y - Young Onset: The hallmark of hereditary cancer. Cancer in the young implies a genetic cause.
• Z - Zoonosis: Not relevant to MEN 2, but 'Z' is for Zero Tolerance of missed phaeochromocytoma screening!

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