What is Multiple Endocrine Neoplasias Type 4?
Multiple endocrine neoplasia, or MEN, is a set of conditions that can be passed down through families. These conditions involve issues across a variety of hormonal and non-hormonal diseases. Depending on the symptoms and genetic mutation, MEN is divided into different types.
The most common type is MEN type 1 (MEN1). This is marked by a high level of calcium in the blood due to overactive parathyroid glands, a benign growth in the pituitary gland (a part of the brain that controls hormone levels), and tumours in the pancreas that can affect hormone production.
MEN type 2 (MEN2) is less common and can be further split into MEN2A and MEN2B. MEN2A features a type of thyroid cancer, a tumour in the adrenal glands (small glands that sit on top of the kidneys and produce hormones), and high blood calcium levels. MEN2B is recognised by thyroid cancer, the same adrenal gland tumour, body shape that resembles Marfan syndrome (tall and slim with long arms, legs and fingers) and nerve cell growths on the lips, tongue, and intestines.
MEN type 4 (MEN4) is the most recently discovered type. Even though it shows similar symptoms to MEN1, MEN4 is very rare. The key difference involves different gene mutations. In MEN1, there’s a mutation in the MEN1 gene, whereas, in MEN4, the mutation is in a gene known as CDKN1B. High blood calcium levels are the main symptom of MEN4, along with tumours in the pituitary gland. It can also be associated with less frequent tumours in the adrenal glands, kidneys, and sex organs. Compared with other types of MEN, like MEN1, MEN4 is not very often reported in medical studies.
What Causes Multiple Endocrine Neoplasias Type 4?
Mutations in a gene called CDKN1B can lead to a condition called MEN4. in humans. This gene, which is found on chromosome 12p13.1, produces a protein known as p27. This protein is a cell-cycle regulator, meaning it helps control how cells grow and divide. The CDKN1B gene functions as a tumor suppressor gene — it works to prevent uncontrolled cell growth that can lead to the formation of tumors. If there are mutations in CDKN1B, it can lead to reduced levels of the p27 protein, which can in turn result in uncontrolled cell growth.
This connection between the CDKN1B gene and tumor development was first discovered in rat studies. Researchers have found that when the functions of p27 (and another protein, p18) are lost, the rats developed multiple tumors in various glands, including the pituitary, thyroid, adrenal, and parathyroid glands. In 2002, a syndrome involving multiple glands that was believed to be a combination of MEN1 and MEN2, was found in rats that didn’t have mutations in the MEN1 or RET genes. This syndrome was named “MENX”.
In 2006, after further studying this syndrome in rats, researchers traced it to a specific region on chromosome 4 where the CDKN1B gene is located. They also discovered that the disorder was passed down through generations in an autosomal recessive pattern, meaning an individual must receive two copies of the faulty gene (one from each parent) to develop the disease. Around the same time, researchers reported the first case of MEN4 in humans in a family who did not have any ME1 gene mutation, but did have a CDKN1B mutation along with multiple endocrine neoplasias and renal angiomyolipomas, which are noncancerous tumors that develop in the kidney.
Lastly, in 2008, the MENX syndrome was renamed MEN4. Recent studies have reported 16 mutations involved in MEN4. This research indicates that MEN4 is inherited in an autosomal dominant pattern in humans, meaning that an individual needs only one copy of the faulty gene from one parent to inherit the disease. The most common symptoms of MEN4 include hyperparathyroidism (an overactive parathyroid), pituitary tumors, and neuroendocrine tumors in the gastrointestinal tract and pancreas.
Risk Factors and Frequency for Multiple Endocrine Neoplasias Type 4
MEN4 is a recently identified syndrome, similar to MEN1 but without the typical genetic mutation found in MEN1. It’s extremely rare, with MEN1 itself only reported in about 0.02 to 0.2 out of 1000 people. Around 3% of patients with features related to MEN1 have been found to have a mutation in the CDKN1B gene, which characterizes MEN4.
Because MEN4 is very rare and likely underdiagnosed, it’s difficult to determine how common it is or at what age symptoms typically first appear. It’s possible that MEN4 develops earlier than MEN1, but current research is inconsistent, and more studies are needed to be sure.
Signs and Symptoms of Multiple Endocrine Neoplasias Type 4
If you suspect you have MEN4, a condition that can show up differently in different members of the same family, it’s important to give your doctor a detailed family health history. They will want to know if any family members have had symptoms or disorders associated with MEN4.
The doctor will check for signs of too much calcium in your blood due to an overactive parathyroid gland, which could cause kidney stones and bone loss. They’ll also look for signs of pituitary tumors, such as changes in your vision, and signs of neuroendocrine tumors in your pancreas, such as heartburn.
They’ll also ask about your own health history, including stomach ulcers and cancer, especially of the breast or reproductive organs, and any surgeries you may have had.
In the physical examination, the doctor will check for signs of over-active pituitary disease, visual problems, neck lumps, previous surgical scars, and autoimmune diseases. Though, so far, there have been no reports of skin changes associated with MEN4. It’s important to note that the physical examination can sometimes be normal, so a detailed personal and family medical history is really crucial for diagnosis.
Testing for Multiple Endocrine Neoplasias Type 4
MEN4 is a condition that is a lot like MEN1. Both of these conditions have similarities in how they are identified and examined for related health conditions. The tests include ones for parathyroid, pituitary, neuroendocrine, and reproductive organ tumors. Carcinoid tumors and meningioma (a type of brain or spinal tumor) can also occur in people with MEN4.
Let’s take a look what these evaluations mean in human body context:
If we begin from the parathyroid gland, the most common sign of MEN4 is a condition known as primary hyperparathyroidism. To find out if a patient has this condition, doctors would typically conduct various lab tests related to blood calcium levels, parathyroid hormone levels, vitamin D levels, and others. Once these results come in, usually an ultrasound of the parathyroid glands is recommended. If the first two tests don’t give a clear answer, a specialized kind of scan or CT could be considered. However, the timing is also important. It’s suggested that screening for high parathyroid levels should start at age 15 in patients diagnosed with MEN4. If necessary, bone density might also be assessed.
When it comes to pituitary gland, the evaluation usually involves testing specific hormones related to it. If initial tests suggest excess hormone, additional tests like an oral glucose tolerance test and an overnight dexamethasone suppression test might be necessary. Occasionally, visual fields may need to be assessed. The imaging study of the pituitary gland could also include MRI. The screening for pituitary gland health issues can start during adolescence.
In some instances, gastrointestinal and pancreatic neuroendocrine tumors have been reported in MEN4. Gastrinomas are most common of these. The screening for pancreatic neuroendocrine tumors should be conducted as per the protocol for MEN1. Some of the recommended tests include checking fasting gastrointestinal hormones annually, CT, MRI, and other types of scans, depending on the specific situation and what services are available.
While it is possible for MEN4 to affect multiple organs, guidance on how to evaluate tumors in these organs is currently undeveloped due to limited available information. Therefore, decisions about these evaluations should be made on a case-by-case basis.
Finally, certain genetic tests, such as those for the CDKN1B gene, could be beneficial in all cases when MEN1 is absent. It might also be beneficial for all first-degree relatives of patients with MEN4 to have these genetic tests.
Treatment Options for Multiple Endocrine Neoplasias Type 4
MEN4, or Multiple Endocrine Neoplasia type 4, is a condition that affects specific glands in your body. Its treatment and management largely depend on which gland it is affecting:
Parathyroid Gland
There currently isn’t any specific advice on how to treat hyperparathyroidism (overactive parathyroid glands) in patients with MEN4. However, indications for surgery, called a parathyroidectomy, are the same as for patients diagnosed with another condition, MEN1. Each surgery is personalized to the patient and should be performed by a surgeon who specializes in endocrine disorders.
Pituitary Gland
If MEN4 affects the pituitary gland, it’s treated in much the same way as any other pituitary tumor. If the tumor is active and releasing hormones or is causing vision problems, physicians will recommend surgery. Surgery, known as a “transsphenoidal” surgery, is performed through the sphenoid sinus, a hollow space in your skull behind the nasal passages and below the brain. Medication treatment may include drugs such as somatostatin receptor analogs (for example, octreotide or lanreotide) in the case of acromegaly and dopamine agonists (like cabergoline or bromocriptine) for prolactinomas. If the pituitary tumor is aggressive, radiation therapy might be considered.
Pancreas
In cases where MEN4 affects the pancreas, its treatment is often similar to that of MEN1. The tumors resulting from this condition may cause peptic ulcers due to an overproduction of stomach acid, leading to a condition known as Zollinger-Ellison syndrome. If the tumors haven’t spread to other parts of the body, surgical removal can potentially cure the condition. The medical approach involves the use of medications such as proton pump inhibitors and somatostatin analogs. There have been no reported cases of insulinoma, VIPoma, glucagonoma, or ectopic ACTH-secreting neuroendocrine tumors in patients with MEN4.
Other Clinical Manifestations
Other clinical manifestations linked to MEN4, such as adrenal tumor, thyroid, testicular cancer, carcinoid, meningioma, or colon cancer, are treated based on the organ affected. Unfortunately, there isn’t any specific advice for treating these additional manifestations due to a lack of scientific study on the topic.
What else can Multiple Endocrine Neoplasias Type 4 be?
When trying to figure out what’s causing certain symptoms, doctors may consider several different conditions. These could include:
- MEN1 disease,
- Neurofibromatosis type 1,
- Tuberous sclerosis,
- Von Hippel-Lindau syndrome, and
- Primary hyperparathyroidism that’s not linked with any other condition.
What to expect with Multiple Endocrine Neoplasias Type 4
There currently isn’t enough information available to predict the long-term outcome of MEN4, a type of genetic disorder. We’re not even sure when disease symptoms typically start. One study by Frederiksen and colleagues suggests that MEN4 might begin earlier than a similar disorder called MEN1. However, another study by de Laat and team found that patients with symptoms of MEN1, but without the actual disease’s genetic mutation, showed signs of the disease later in life and lived longer.
Although it’s possible that these patients may have had MEN4, we can’t say for sure. As more MEN4 cases are identified and studied, we’ll have a better understanding of the disease.
Possible Complications When Diagnosed with Multiple Endocrine Neoplasias Type 4
People with MEN4 can experience complications due to the impact of the disease itself and any issues after surgery. The disease’s effects can cause systemic and metabolic changes, which might occur due to conditions like acromegaly, Cushing’s disease, primary hyperparathyroidism, and tumors in the digestive system and pancreas.
Having primary hyperparathyroidism can cause bone weakness and kidney stones. Disorders related to the pituitary gland can result in decreased vision, visual field defects (reduced side (peripheral) vision), lower pituitary gland function, and related problems.
Common Complications:
- Systemic and metabolic changes due to acromegaly or Cushing’s disease
- Primary hyperparathyroidism leading to bone weakening and kidney stones
- Functional tumors in the digestive system and pancreas
- Decreased vision and vision field defects from pituitary disorders
- Lower pituitary gland function and related issues
- Complications following surgery
Preventing Multiple Endocrine Neoplasias Type 4
MEN4 is an uncommon condition that causes tumors to grow in various hormone-producing glands in the body. It’s crucial for patients to understand the significance of genetic testing in this context. They should be educated about MEN4’s varied health-related issues and how these might affect them and their families.
Patients are strongly recommended to share their diagnosis with their family and consider undergoing genetic testing. They should have the freedom to discuss their diagnosis with a specialist in genetic diseases, or a team focused on genetic conditions. Regular follow-up appointments should be attended by both the patient and their family members to monitor the condition appropriately.
