What is Multiple Endocrine Neoplasias Type 2 (Sipple Syndrome)?
Multiple endocrine neoplasia type 2 (MEN2), or Sipple syndrome, is a rare set of hereditary cancer conditions affecting various hormone-producing organs in the body. The most commonly involved are the thyroid, adrenal glands, and parathyroid glands. This disease was first identified by Dr. Sipple in 1961, who found a strong link between certain types of adrenal and thyroid gland cancers. Later, it was discovered that MEN2 could impact other tissues and organs not traditionally linked to hormone production, like the gut or skin.
MEN2 is an inherited condition that’s dominant, meaning an affected person has a 50% chance of passing it to their offspring. It varies in seriousness from person to person, and even though it’s a rare condition, it is crucial to identify it for proper treatment of the patient and health assessments for their family members.
MEN2 is divided into two main types: MEN2A and MEN2B. Both types affect the thyroid and adrenal glands. However, MEN2A also leads to overactive parathyroid glands (hyperparathyroidism) in 20% to 30% of cases. Additionally, there are four subtypes of MEN2A:
– Classic MEN2A
– MEN2A paired with a skin condition known as cutaneous lichen amyloidosis (CLA)
– MEN2A paired with a intestinal disorder known as Hirschsprung disease (HD)
– A familial form of thyroid cancer (FMTC)
In both types of the condition, MEN2A and MEN2B, there’s a risk of developing multiple tumors in all organs where a gene known as RET is active.
What Causes Multiple Endocrine Neoplasias Type 2 (Sipple Syndrome)?
The rearranged during transfection (RET) protein, found on chromosome 10q11.2, plays an important role in growth and development, especially for cells arising from the neural crest, which are cells in embryos that contribute to the development of several vital tissues in the body. Some genetic mutations can affect different areas of this RET protein and how it communicates signals inside the body. Unlike many genetic predispositions to cancer, which happen when “loss-of-function” mutations deactivate cancer-suppressing proteins, the RET mutations in a condition called MEN2 actually increase the activity of this protein.
The RET protein is structured with an outer part that interacts with the environment outside of the cell and an inner part that operates within the cell. The outer part has a few different domains, areas with specific functions, that enable the protein to bind with other molecules and adhere to cells. The inner part has two domains called TK1 and TK2 which are key for the protein’s function inside the cell.
The RET protein gets activated when it binds with one of its four ligand partners – molecules that can create a signal by binding to a target protein. This binding triggers a series of reactions, leading to changes in other proteins inside the cell. Mutations in the RET protein can cause a condition called MEN2A. Most of the associated mutations happen in the part of the protein located outside the cell, while mutations in one of the inner parts of the protein can cause tumors associated with a version of MEN2A called MEN2B.
A single mutation, known as M918T, found in a specific area (exon 16) of the RET gene, is responsible for over 95% of Men2B cases. Different mutations have different risk levels, which can significantly impact screenings, diagnosis, and treatment. For instance, the M918T mutation is considered high-risk for MEN2B, and identifying this can help doctors to focus on aggressive screenings and treatment in order to reduce harm and possibility of death resulting from this condition.
Risk Factors and Frequency for Multiple Endocrine Neoplasias Type 2 (Sipple Syndrome)
MEN2, a medical condition, can be found in about 1 out of every 35,000 people across the world. Within the United States, this figure ranges from 1 out of every 30,000 to 50,000 people. There’s less known about MEN2B, another type of this condition. It’s believed that MEN2B occurs in somewhere between 1 in 600,000 to 1 in 4 million people.
Signs and Symptoms of Multiple Endocrine Neoplasias Type 2 (Sipple Syndrome)
If you are diagnosed with either medullary thyroid cancer (MTC) or pheochromocytoma, especially if you’re younger than 35, you may have MEN2A or MEN2B. These conditions are often suspected if you have a lump in your thyroid, swollen lymph nodes in your neck, or a family history of MTC. Doctors often check for specific gene changes (RET proto-oncogene mutations) that can indicate either MEN2A or MEN2B. If you have been diagnosed with pheochromocytoma at an earlier age than what is typical, you should also be tested for MEN2A and MEN2B. Symptoms of pheochromocytoma, such as headaches, anxiety, profuse sweating, palpitations, and high blood pressure, particularly between the ages of 25 and 32, can suggest the need to test for MEN2.
The doctor will ask about your medical history and check if any of your family members have had the conditions just mentioned. Other physical signs that can indicate MEN2B include:
- A higher than normal length of the body compared to width (Marfanoid habitus)
- Red spots (mucosal neuromas) around the mouth and on the tongue
- Excessive flexibility in the joints (joint hyperlaxity)
Interestingly, people with MEN2B typically don’t have problems with the lenses of their eyes or their aorta, which is common in individuals with Marfan syndrome. MEN2A may also be identified via specific skin changes, such as itchy, scaling, and dark spots on the skin between your shoulder blades. These are symptoms of a skin condition called CLA, which is often associated with MEN2A.
Testing for Multiple Endocrine Neoplasias Type 2 (Sipple Syndrome)
When it comes to conditions known as MEN2, doctors mainly test patients who show classic symptoms for two reasons. First, they want to find any associated common tumors early on. Catching these tumors early reduces overall harm and the risk of death. Second, they’d like to detect any genetic changes that might be present so they can test other family members. That way, appropriate preventative care and surgeries, like thyroid removal, can be provided promptly.
In most cases of MEN2, the first sign is a type of thyroid cancer known as medullary thyroid cancer (MTC). If a doctor identifies features of MTC (for example, a solitary, non-functioning thyroid lump and swollen neck lymph nodes), they may perform a biopsy, a simple procedure where a small sample is taken from the lump for further study. They might also recommend genetic testing for both the patient and close family members to identify any specific genetic changes that can lead to MEN2.
Sometimes, an individual might not have any symptoms but a test reveals a high level of a hormone called calcitonin in their blood. Genetic tests might also reveal a person’s risk of MEN2 due to a family history of the disease. Even in these cases, MTC often reveals itself in the form of abnormal growth of C-cells, a particular type of cells found in the thyroid.
Certain tumors such as pheochromocytoma, a rare tumor that occurs in the adrenal glands, are less likely to show up before MTC in people with MEN2. If someone has been diagnosed with pheochromocytoma, the doctor may recommend further screening for other tumors as well as certain genetic tests.
Primary hyperparathyroidism, a condition involving the overproduction of parathyroid hormone that leads to high levels of calcium in the blood, is not a good enough reason for further testing alone. It has a weak correlation with MEN2A and no correlation with MEN2B.
Genetic testing is done to identify any genetic changes in the RET gene which drive MEN2 cancers. The type of genetic changes can provide valuable information about disease characteristics and can also save time in screening family members to know when to start checking them for associated tumors and timings for preventative surgery.
MEN2A and MEN2B follow a specific pattern when it comes to genetic testing. For suspected MEN2A cases, testing starts with looking for common changes in specific parts of the RET gene and if those are not found, they continue looking for other common changes in a specified order. A similar pattern is followed for MEN2B cases.
In some cases, even if no identifiable RET changes are found, having at least two classic features of MEN2A or having majority of clinical features of MEN2B is enough for a clinical diagnosis.
Genetic testing could be considered for first-degree family members of a patient with proven RET gene changes, parents whose infants or young children show signs of MEN2B, and in families where infants or young children have a certain disease of the large intestine known as Hirschsprung disease.
Upon receiving positive genetic test results, biochemical and radiological screening for other tumors may start. In children, the goal is to perform a preventive thyroid removal surgery before MTC develops or when it is still confined to the thyroid gland.
Children deemed at high-risk begin monitoring at 3 years of age, while those at moderate risk start at 5 years of age. The monitoring includes an annual physical examination, a neck ultrasound, and measure of serum calcitonin concentration. If serum calcitonin level is above the upper limit of normal, it often suggests a need for surgery.
The risk of developing pheochromocytoma varies depending on the genetic mutation. Prevention programs allow these tumors to be diagnosed at a young age, even before symptoms appear.
For hyperparathyroidism (only associated with MEN2A), which is often mild and doesn’t show symptoms, the average age at diagnosis is 33 years. Screening begins at age 11 for high-risk patients and by age 16 for moderate-risk patients, primarily through measuring serum calcium levels.
Treatment Options for Multiple Endocrine Neoplasias Type 2 (Sipple Syndrome)
Medullary Thyroid Carcinoma (MTC) is a disease commonly seen in patients with genetic disorders known as MEN2A and MEN2B. In MTC, multiple tumors affect both sides of the thyroid gland, a butterfly-shaped organ in the neck that produces important hormones. Patients with the MEN2B variation often have a more aggressive form of the disease, and how severe the condition is will depend on the specific type of genetic mutation a person has.
When it comes to treatment, patients with MEN2B should get surgery to remove the thyroid gland and nearby lymph nodes, even if there is no sign of disease in these nodes, when they are one year old. This is suggested because the disease can spread quickly in these patients, sometimes even before they turn one.
Similarly, patients with high-risk mutations of MEN2A should also consider the same surgery, but it is usually done when they reach the age of 5. For patients with moderate-risk mutations, the surgery can wait until they are in late childhood or early adulthood. The goal of this treatment is to remove the thyroid gland before the disease advances to a stage where surgery is no longer an option.
Before surgery, doctors should check for another related condition called pheochromocytoma, a rare tumor that develops in the adrenal glands. If it is present, it should be removed first.
About 40% of patients with MEN2A and 50% with MEN2B develop pheochromocytoma. Again, it’s often found on both adrenal glands and is more widespread than the form of the disease that occurs in people without these genetic disorders. If the patient has tumors on both adrenal glands, or if they have tumors on one side but a family history of aggressive bilateral tumors, both adrenal glands should be removed. But if a patient has a tumor only on one side and the other adrenal gland looks normal, they should only need to have the affected gland removed.
In preparation for adrenal gland surgery, patients should be given certain medication known as an alpha-blocker beforehand. During surgery, they might need extra corticosteroids, which are hormones that help our bodies deal with stress and maintain normal functions like keeping blood pressure steady and managing the immune system.
Another condition associated with MEN2A is Primary Hyperparathyroidism, which affects about 10% to 25% of patients. This condition, which leads to abnormally high levels of calcium in the blood, doesn’t occur in MEN2B patients at all. The disease is typically mild and shows up late, often without causing any noticeable symptoms. Because of this, doctors don’t recommend removing the parathyroid glands (tiny glands located near the thyroid that regulate the level of calcium in our bodies) unless the patient starts to show signs of severe symptoms, like worsening high blood calcium levels, bone loss, and kidney problems. Instead, these patients should have regular checks of their blood calcium levels, kidney function, and bone density every year or two. If parathyroid surgery becomes necessary, doctors should again check for existing pheochromocytoma, and if it is present, it needs to be removed before the parathyroid glands.
What else can Multiple Endocrine Neoplasias Type 2 (Sipple Syndrome) be?
There are several genetic disorders that can be inherited within families, such as:
- Familial hyperparathyroidism
- Familial hypocalciuric hypercalcemia
- Multiple endocrine neoplasia type 1
- Sturge-Weber syndrome
- Tuberous sclerosis
- Von Hippel-Lindau syndrome
- Von Recklinghausen disease
These disorders can cause a variety of health problems, and it’s important to know your family health history to ensure early detection and treatment.
