Lymphangioleiomyomatosis (LAM) is a rare lung disease that affects mostly women of childbearing age (the years between puberty and menopause when it is possible to become pregnant).

In people who have LAM, abnormal muscle-like cells begin to grow out of control in the lungs and other parts of the body. Over time, these LAM cells can destroy healthy lung tissue. As a result, fluid-filled pockets called cysts may develop, preventing air from moving freely in and out of the lungs. This can lower the amount of oxygen that reaches the rest of the body.

There are two types of LAM.

• TSC-LAM occurs in some people who inherit a rare genetic disease called tuberous sclerosis complex (TSC).
• Sporadic LAM is caused by a genetic mutation (change) that occurs spontaneously during a person’s life but cannot be passed on to children.

Symptoms of LAM may include shortness of breath, tiredness, chest pain, cough, and respiratory failure. LAM can be difficult to diagnose, as the symptoms are often similar to asthma, bronchitis, and other lung diseases.

LAM can develop slowly. You may not discover you have LAM until you feel stabbing chest pain and have a hard time breathing. These symptoms mean that air has leaked into the space between the chest wall and the lung, causing a collapsed lung (pneumothorax). This common complication of LAM requires immediate treatment.

If you are diagnosed with LAM, your healthcare provider may prescribe medicine to help prevent more damage to your lungs and to treat symptoms or health problems. Over time, LAM cells can cause permanent damage to the lungs or can lead to respiratory failure, which happens when your organs don’t receive enough oxygen to work well.

Lymphangioleiomyomatosis (LAM) is a condition that affects the lungs, the kidneys, and the lymphatic system. The lymphatic system consists of a network of vessels that transport lymph fluid and immune cells throughout the body. Lymph fluid helps exchange immune cells, proteins, and other substances between the blood and tissues.

LAM is found almost exclusively in women. It often occurs as a feature of an inherited syndrome called tuberous sclerosis complex. When LAM occurs alone it is called isolated or sporadic LAM.

Signs and symptoms of LAM most often appear during a woman's thirties. Affected women have an overgrowth of abnormal smooth muscle-like cells (LAM cells) in the lungs, resulting in the formation of lung cysts and the destruction of normal lung tissue. They may also have an accumulation of fluid in the cavity around the lungs (chylothorax).

The lung abnormalities resulting from LAM may cause difficulty breathing (dyspnea), chest pain, and coughing, which may bring up blood (hemoptysis). Many women with this disorder have recurrent episodes of collapsed lung (spontaneous pneumothorax). The lung problems may be progressive and, without lung transplantation, may eventually lead to limitations in activities of daily living, the need for oxygen therapy, and respiratory failure. Although LAM cells are not considered cancerous, they may spread between tissues (metastasize). As a result, the condition may recur even after lung transplantation.

Women with LAM may develop cysts in the lymphatic vessels of the chest and abdomen. These cysts are called lymphangioleiomyomas. Affected women may also develop tumors called angiomyolipomas made up of LAM cells, fat cells, and blood vessels. Angiomyolipomas usually develop in the kidneys. Internal bleeding is a common complication of angiomyolipomas.

LAM occurs in approximately 30 percent of women with tuberous sclerosis complex. Sporadic LAM, which occurs without tuberous sclerosis complex, is estimated to affect 3.3 to 7.4 per million women worldwide. This condition may be underdiagnosed because its symptoms are similar to those of other lung disorders such as asthma, bronchitis, and chronic obstructive pulmonary disease.

Most often, LAM is caused by mutations (changes) in the structure of one of two tuberous sclerosis complex (TSC) genes, called TSC1 and TSC2. Abnormal muscle-like cells that carry these mutations appear and grow out of control in the lungs, kidneys, or lymph nodes. These LAM cells may initially develop in the uterus or elsewhere, but when they travel to the lungs, they produce the respiratory symptoms of LAM.

Researchers believe the hormone estrogen plays a role, because the condition affects mostly women between puberty and menopause. The condition also gets worse during pregnancy and after using medicines with estrogen, such as birth control. After menopause, LAM sometimes stops getting worse.

Normal Function

The TSC1 gene provides instructions for producing a protein called hamartin. Within cells, hamartin interacts with a protein called tuberin, which is produced from the TSC2 gene. These two proteins help control cell growth and division (proliferation) and cell size. Proteins that normally prevent cells from growing and dividing too fast or in an uncontrolled way are known as tumor suppressors. Hamartin and tuberin carry out their tumor suppressor function by interacting with and regulating a wide variety of other proteins.

Health Conditions Related to Genetic Changes

Lymphangioleiomyomatosis

TSC1 gene variants (also known as mutations) can cause a disorder called lymphangioleiomyomatosis (LAM), although variants in the TSC2 gene appear to be responsible for most cases of this disorder. This destructive lung disease is caused by the abnormal overgrowth of smooth muscle-like tissue in the lungs. It occurs almost exclusively in women, causing coughing, shortness of breath, chest pain, and lung collapse.

LAM can occur alone (isolated or sporadic LAM) or in combination with a condition called tuberous sclerosis complex (described below). Researchers suggest that sporadic LAM can be caused by a random variant in the TSC1 gene that occurs very early in development. As a result, some of the body's cells have a normal version of the gene, while others have the altered version. This situation is called mosaicism. When a variant occurs in the other copy of the TSC1 gene in certain cells during a woman's lifetime (a somatic variant), she may develop LAM.

Tuberous sclerosis complex

Hundreds of variants in the TSC1 gene have been identified in individuals with tuberous sclerosis complex, a condition characterized by developmental problems and the growth of noncancerous (benign) tumors in many parts of the body. Most of these variants involve either small deletions or insertions of DNA in the TSC1 gene. Some variants create a premature stop signal in the instructions for making hamartin.

People with TSC1-related tuberous sclerosis complex are born with one altered copy of the TSC1 gene in each cell. A TSC1 gene change prevents the cell from making functional hamartin from that copy of the gene. Enough hamartin is usually produced from the other, normal copy of the TSC1 gene to regulate cell growth effectively. For some types of tumors to develop, a second variant involving the other copy of the gene must occur in certain cells during a person's lifetime.

When both copies of the TSC1 gene are altered in a particular cell, that cell cannot produce any functional hamartin. The loss of this protein allows the cell to grow and divide in an uncontrolled way to form a tumor. A shortage of hamartin also interferes with the normal development of certain cells. In people with TSC1-related tuberous sclerosis complex, a second TSC1 gene variant typically occurs in multiple cells over an affected person's lifetime. The loss of hamartin in different types of cells disrupts normal development and leads to the growth of tumors in many different organs and tissues, leading to the signs and symptoms of tuberous sclerosis complex.

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Other disorders

Inherited variants in the TSC1 gene can cause a disorder known as focal cortical dysplasia of Taylor balloon cell type. This disorder involves malformations of the cerebrum, the large, frontal part of the brain that is responsible for thinking and learning. Focal cortical dysplasia causes severe recurrent seizures (epilepsy) in affected individuals.

Other Names for This Gene

• hamartin
• KIAA0243
• TSC1_HUMAN
• tuberous sclerosis 1

Genomic Location

Normal Function

The TSC2 gene provides instructions for producing a protein called tuberin. Within cells, tuberin interacts with a protein called hamartin, which is produced from the TSC1 gene. These two proteins help control cell growth and division (proliferation) and cell size. Proteins that normally prevent cells from growing and dividing too fast or in an uncontrolled way are known as tumor suppressors. Hamartin and tuberin carry out their tumor suppressor function by interacting with and regulating a wide variety of other proteins.

Health Conditions Related to Genetic Changes

Lymphangioleiomyomatosis

TSC2 gene variants (also known as mutations) cause most cases of a disorder called lymphangioleiomyomatosis (LAM). This destructive lung disease is characterized by the abnormal overgrowth of smooth muscle-like tissue in the lungs. It occurs almost exclusively in women, causing coughing, shortness of breath, chest pain, and lung collapse.

LAM can occur alone (isolated or sporadic LAM) or in combination with a condition called tuberous sclerosis complex (described below). Researchers suggest that sporadic LAM is caused by a random variant in the TSC2 gene that occurs very early in development. As a result, some of the body's cells have a normal version of the gene, while others have the altered version. This situation is called mosaicism. When a variant occurs in the other copy of the TSC2 gene in certain cells during a woman's lifetime (a somatic variant), she may develop LAM.

Tuberous sclerosis complex

More than a thousand variants in the TSC2 gene have been identified in individuals with tuberous sclerosis complex, a condition characterized by developmental problems and the growth of noncancerous tumors in many parts of the body. Most of these variants insert or delete a small number of DNA building blocks (base pairs) in the TSC2 gene. Other variants change a single base pair in the TSC2 gene or create a premature stop signal in the instructions for making tuberin.

People with TSC2-related tuberous sclerosis complex are born with one altered copy of the TSC2 gene in each cell. A TSC2 gene variant prevents the cell from making functional tuberin from that copy of the gene. Enough tuberin is usually produced from the other, normal copy of the TSC2 gene to regulate cell growth effectively. For some types of tumors to develop, a second variant involving the other copy of the gene must occur in certain cells during a person's lifetime.

When both copies of the TSC2 gene are altered in a particular cell, that cell cannot produce any functional tuberin. The loss of this protein allows the cell to grow and divide in an uncontrolled way to form a tumor. A shortage of tuberin also interferes with the normal development of certain cells. In people with TSC2-related tuberous sclerosis complex, a second TSC2 gene variant typically occurs in multiple cells over an affected person's lifetime. The loss of tuberin in different types of cells disrupts normal development and leads to the growth of tumors in many different organs and tissues, leading to the signs and symptoms of tuberous sclerosis complex.

Other Names for This Gene

• PPP1R160
• TSC2_HUMAN
• tuberin
• tuberous sclerosis 2

Genomic Location

People often begin to show symptoms of LAM between 20 and 40 years old. If left untreated, LAM can cause serious and life-threatening health problems.

If you have LAM, you may have one or more of these common symptoms:

• Chest pain or aches that get worse when you breathe in
• Extreme tiredness
• Frequent coughing, which can produce bloody phlegm or mucus in your lungs
• Severe pain or tightness in the chest and shortness of breath, which can be symptoms of a collapsed lung (pneumothorax)
• Shortness of breath, which at first may happen only during high-energy activities but over time may start after simple activities, such as dressing and showering
• Wheezing or a whistling sound when you breathe

You may feel the following symptoms in other parts of the body that are caused by LAM cells:

• Abdominal pain: Many people who have LAM get benign (noncancerous) tumors in their kidneys. If these tumors grow large enough, they can lead to bleeding in the kidneys or fluid buildup, which can cause pain in the abdomen.
• Lymph nodes that may be larger than normal: Usually, these larger-than-normal lymph nodes develop in body locations where they cannot be felt, such as the chest. Rarely, larger-than-normal lymph nodes may develop in places where they can be felt, such as in the neck or under the arms.

Your healthcare provider will diagnose LAM based on your medical history and the results from diagnostic tests and procedures. You may also see a pulmonologist (a healthcare provider specializing in lung diseases and conditions) who has experience providing care to people who have LAM.

Medical history

Your healthcare provider will ask you about your medical history to see whether you have symptoms of LAM. They may ask how long you have had symptoms and whether your symptoms have become worse over time.

Diagnostic tests

Your provider may order tests to measure how well your lungs are working and determine whether your lungs are delivering enough oxygen to your blood.

Chest CT scan

For an accurate diagnosis, a high-resolution computed tomography (HRCT) scan is essential. It creates detailed pictures of your lungs and the inside of your chest. Computers can combine these pictures to create three-dimensional (3D) models showing the size, shape, and position of your lungs and other structures in your chest. Your healthcare provider may diagnose you with LAM if the chest HRCT shows thin-walled cysts (fluid-filled pockets) in your lungs.

Chest X-ray

A chest X-ray is a fast and painless imaging test to look at the structures in and around your chest.

A chest X-ray may look normal in the early stages of LAM. As the disease gets worse, the X-ray may be used to find cysts in your lungs and monitor any changes over time. Your healthcare provider may use a chest X-ray to look for complications of LAM, such as fluid in your lungs or air in the chest cavity that collapses your lung (a pneumothorax).

Lung function tests

Lung function tests can help your healthcare provider determine how well your lungs are working. These tests may help diagnose certain lung conditions or diseases, including LAM.

Blood tests

Your healthcare provider may order blood tests, such as a test for vascular endothelial growth factor D (VEGF-D) that looks for increased VEGF-D levels in your blood. Higher levels of VEGF-D can stimulate the growth of new blood vessels, which can enable the cells that cause LAM cells to spread in the body. About 70% of patients with LAM have raised VEGF-D levels.

Procedures

If other tests cannot diagnose LAM, your healthcare provider may recommend a lung biopsy , but only when an absolutely certain diagnosis is required.

• A lung biopsy removes small pieces of your lung to check for LAM cells. Your provider may do an open lung biopsy, which involves making a cut in your chest wall between your ribs. With a transbronchial biopsy, your provider inserts a long tube down your windpipe and into your lungs. Whenever possible, the transbronchial biopsy is the preferred approach. Your healthcare provider can also diagnose LAM using results from biopsies of other tissues, such as the lymph nodes.
• Video-assisted thoracoscopic surgery (VATS) may be done to remove small pieces of your lung to check for LAM cells, if your provider suspects LAM but is not able to diagnose using a traditional open lung or transbronchial biopsy. In the VATS procedure, your provider makes several small cuts in your chest wall and inserts a small, lighted tube with tools and a camera on the end. The camera takes pictures of the lungs to guide your provider while they do the biopsy.

Tests for other medical conditions

Your healthcare provider may need to order other diagnostic tests to determine whether you have a related condition called tuberous sclerosis complex (TSC), which can lead to LAM, or to rule out another condition.

• CT scans or magnetic resonance imaging (MRI) scans of your head can help your provider determine whether you have TSC. People with TSC often have tumors in the brain and other parts of the body.
• Genetic testing identifies mutations (changes) in your TSC1 and TSC2 genes to help your provider confirm that you have LAM and not another lung disease.
• Thoracentesis uses a needle to collect fluid samples from the lining of your lungs. If your chest imaging tests show that you have fluid building up in the space between the lung and the chest wall (called pleural effusions), your provider may order thoracentesis to collect this pleural fluid for analysis.

LAM is a progressive disease, meaning it gets worse over time. There is no cure for LAM, but there are effective medicines that can help relieve LAM symptoms and prevent complications. Oxygen therapy or a lung transplant may also be treatment options.

Medicines

Your healthcare provider may prescribe medicines to open up your airways and make it easier for you to breathe.

• Bronchodilators are medicines that can help relax the muscles around the airways if you are wheezing or having trouble breathing.
• Sirolimus is a type of medicine called an mTOR inhibitor. Sirolimus may help control the abnormal growth and movement of LAM cells. The medicine may also help lung function, shrink kidney and lymph node growths, and reduce fluid in your lungs. Side effects can include diarrhea, nausea, acne, high blood cholesterol, swelling of your mouth and lips, and fluid buildup in your legs. Sirolimus may also affect your ovaries, liver, and kidneys and raise your risk of infections.

Sirolimus is the only drug approved for the treatment of LAM by the U.S. Food and Drug Administration (FDA). Everolimus, a different mTOR inhibitor approved by the FDA for treating benign brain tumors associated with TSC, is also sometimes used to treat LAM. Talk with your provider about the benefits and risks of sirolimus and everolimus and whether either medicine is an option for you.

Oxygen therapy

Your healthcare provider may recommend oxygen therapy to increase the amount of oxygen your lungs receive and deliver to your blood. At first, you may only need oxygen therapy during high-energy activities. It may also be helpful while sleeping. Eventually, you may need full-time oxygen therapy.

Lung transplant

Some people with severe lung damage from advanced LAM may be eligible for a lung transplant.

There is no way to prevent LAM. If you have TSC, your healthcare provider may recommend that you not smoke or take medicine with estrogen. This may help slow down the development of LAM. Medicines may stop abnormal LAM cells from increasing in number and may reduce their size. If you have TSC-LAM, your provider may recommend genetic counseling before you get pregnant to help you understand the risk of passing TSC and LAM on to your children.

The outlook for people who have LAM is much better today than it was in the past. Diagnosis and treatments have advanced. Many people who have LAM are living longer and with fewer complications.

Receive routine follow-up care

It is important that you follow your healthcare provider’s instructions for your treatment and see your provider regularly to monitor your health.

• Follow your treatment plan. It may take several months for your body to respond to treatment. If you stop taking your medicines, your symptoms may return or get worse.
• Get regular vaccinations for lung health. Talk with your provider about getting a pneumonia vaccine, the COVID-19 vaccine, and a yearly flu shot.

Take care of your mental health

Living with LAM may cause fear, anxiety, depression, and stress. Your healthcare provider can evaluate how your condition is affecting your activity level and your mental health. To help improve your quality of life, your provider may recommend steps you can take.

• Get counseling, particularly cognitive behavioral therapy.
• Join a patient support group, which may help you adjust to living with LAM. You can see how other patients manage similar symptoms and their condition. Talk with your provider about local support groups or check with an area medical center.
• Seek support from family and friends, which can help relieve stress and anxiety. Let your loved ones know how you feel and what they can do to help you.
• Take medicines or other treatments. Your provider may recommend medicines, such as antidepressants, or other treatments that can help improve your quality of life.

Adopt healthy lifestyle changes

If you have LAM, it is important that you take good care of your health. Your healthcare provider may recommend that you adopt the following healthy lifestyle changes:

• Choose healthy foods. Eating more fruits, vegetables, and whole grains and fewer saturated fats and added sugars can improve your overall health. A healthy diet can promote weight loss or help you maintain a healthy weight.
• Get physical activity. Physical activity improves bone mineral density, muscle strength, flexibility, and posture. You may also benefit from rehabilitation and aerobic exercise, or training to raise the amount of oxygen in your blood. Before starting any exercise program, ask your provider about what level of physical activity is right for you.
• Quit smoking. If you smoke, stop. Also, try to avoid other lung irritants, such as dust, chemicals, and secondhand smoke. Visit Smoking and Your Heart and Your Guide to a Healthy Heart. For free help to quit smoking, call the National Cancer Institute’s Smoking Quitline at 1-877-44U-QUIT (1-877-448-7848).

Your provider may recommend these lifestyle changes as part of a larger pulmonary rehabilitation program, which they can oversee.

How LAM can affect your health

LAM may lead to serious and life-threatening health problems.

• Collapsed lung: This condition, also known as a pneumothorax, can happen when air leaks into the pleural space in the lungs. Reinflating the lung requires a tube that is inserted into the chest between the ribs. Often, the tube is attached to a suction device. If this procedure does not work or if your lungs repeatedly collapse, you may need surgery to re-expand the lung to normal size. Your provider may recommend a surgical procedure called pleurodesis to help the lungs and chest cavity stick together and prevent future lung collapses.
• Kidney or other tumors: Most kidney tumors are benign (noncancerous), but sometimes they can cause symptoms such as pain or bleeding. If this happens, you may need surgery to remove them. If the bleeding is not too severe, a healthcare provider called a radiologist may be able to use medical imaging equipment to block the blood vessels feeding the kidney tumors. This may cause them to shrink. Women who have LAM may also develop large tumors in the lymph nodes or in other organs, such as the liver.
• Osteoporosis: This condition causes bones to become weak and break easily. Your provider may order tests to measure your bone density. If you have lost bone density, your provider may prescribe medicines or calcium and vitamin D supplements to prevent more bone loss.
• Pleural effusions: These may occur if body fluids collect in the pleural space between the lung and the chest wall. The excess fluid in the chest may cause shortness of breath, because the lung has less room to expand. One form of pleural effusion is known as a chylothorax, which is caused when a certain type of lymphatic fluid (chyle) accumulates in the pleural space.

Prevent complications over your lifetime

• Avoid air travel because it increases your risk of developing pneumothorax that collapses the lung. Symptoms include sudden shortness of breath or severe chest pain. Talk to your provider before air travel or before traveling to places at a higher elevation, where there is less oxygen in the air.
• Avoid scuba diving, which may raise your risk of complications.
• See your provider regularly so they can keep track of any side effects you report and monitor the long-term use of LAM medications.

Pregnancy and birth control planning

Women with LAM can become pregnant, but hormone changes during pregnancy can worsen LAM. Also, women with LAM may be less fertile and have a harder time becoming pregnant. Pregnancy with LAM increases the risk for pneumothorax and chylothorax, may lead to more lung function decline, and raises the chance of preterm delivery. The long-term effects of the medicine sirolimus on mother and child also needs additional study. While many women with LAM have full-term pregnancies, it is important to talk to your healthcare provider if you are thinking of becoming pregnant.

Most providers do not recommend birth control pills containing estrogen to women who have LAM, because estrogen is thought to contribute to or worsen LAM. If you have LAM and are interested in birth control, talk to your healthcare provider about your options.