Disorder Definitions
 
What is Lymphangioleiomyomatosis (LAM)?

Lymphangioleiomyomatosis (LAM), pronounced lim-fan-gee-o-ly-o-my-o-ma-to-sis, is a rare, progressive lung disease that predominantly affects women.  The name of the disease can be broken down into elements that describe the pathology.  “Lymph” refers to the lymph vessels. “Angio” refers to the blood vessels. “Leiomy” means smooth muscle. “Oma” is a tumor. “Tosis” refers to a disease. 

Abnormal growth of smooth muscle cells in the lung characterizes LAM. These cells invade all lung structures and limit flow through the airway, blood, and lymph vessels. The cells also damage the delicate, lacy lung tissues and cause cysts to form.


What causes LAM?

LAM occurs in patients with tuberous sclerosis (Tuberous Sclerosis Complex (TSC)-LAM) or in women who do not have tuberous sclerosis (Sporadic-LAM (S-LAM)).  TSC-LAM is a rare genetic disease that causes tumor growth in the brain, kidneys, heart, eyes, lungs, and skin. Most TSC-LAM patients have a mutation in a gene that codes for a protein called tuberin, and some have mutations in a gene that codes for the protein hamartin.  Approximately 30-80% of patients with TSC will develop cystic changes in their lungs consistent with LAM. S-LAM patients have mutations in the tuberin gene and typically present with more advanced disease than patients with TSC-LAM.


What are the symptoms of LAM?

Some patients have no symptoms, while others have many. LAM causes people to have trouble breathing. Growth of the cells in the lung limits the flow of air, making it harder for oxygen to reach the blood and for carbon dioxide to be eliminated.  The cells also produce substances that dissolve lung tissue.  This causes the formation of cysts. As the disease progresses, cysts near the surface of the lung may rupture.  Patients may develop a collapsed lung or collection of milky fluid, called chyle, in the chest. Patients may also develop benign kidney tumors, swollen lymph nodes, or swelling in the abdomen, legs, ankles, or feet. Most women with LAM have had symptoms for three to five years before receiving their diagnosis. 


How is LAM diagnosed?

LAM is sometimes recognized late because symptoms are similar to other lung diseases. CT scans or a lung biopsy can detect the lung cysts. Many patients are diagnosed after they have had a collapsed lung. There is now a blood test called serum VEGF-D that is helpful for making the diagnosis of LAM in women who have typical cystic changes in their lung.


How common is LAM?

LAM is a disease that occurs mainly in women, of all races and ethnicities, generally in their twenties or thirties. Current estimates suggest that 30,000 - 50,000 S-LAM patients exist worldwide.


What is the natural history of LAM?

LAM is generally a slow, progressive disease. Some patients remain stable over many years, while others decline rapidly. The rate of lung function is affected by menopausal status and by the serum levels of a protein called serum VEGF-D. Many LAM patients eventually develop shortness of breath with daily activities and some will require oxygen therapy. Although not a cure, lung transplantation is an option for many patients.


What is the treatment for LAM?

Recent evidence has shown that a drug called Sirolimus (also known as rapamycin or rapamune), prevents decline in lung function and improves daily functioning in patients with LAM. Patients with abnormal lung function, those who are declining rapidly, and patients with chylous effusions are considered candidates for treatment.


Future

While many questions about LAM remain, the extraordinary progress in understanding LAM has provided hope that we can find a treatment and cure for LAM.

What is Pulmonary Alveolar Proteinosis (PAP) Syndrome?

Pulmonary Alveolar Proteinosis (PAP) is a not a single disease – it is a rare syndrome or condition that can occur in several different diseases. The syndrome is caused by the build up of surfactant in the lungs that makes breathing difficult.

Normally, surfactant is present as a very thin layer on the lung surface. It helps keep the millions of tiny air sacs (alveoli) stay open as we breath. The thin layer of surfactant is maintained by balanced production and destruction inside alveoli.

Alveolar macrophages are special cells inside alveoli that remove excess surfactant from alveoli. This helps keep the surfactant layer thin and useful. Macrophages require stimulation by a protein called GM-CSF in order to function correctly and remove surfactant.

PAP occurs when something happens that disturbs the balance of surfactant production and removal. When this occurs, surfactant builds up inside the alveoli over time. Eventually, the alveoli fill up completely with surfactant leaving no room for the air we breath to enter. The result is that oxygen can’t get into the blood as easily, which causes a feeling of breathlessness.


What causes PAP?

The different diseases in which PAP occur can be divided into three groups: Primary PAP, Secondary PAP, and Disorders of surfactant Metabolism.

Primary PAP occurs when something prevents GM-CSF from stimulating alveolar macrophages. This reduces their ability to remove excess surfactant and causes PAP. There are two diseases in this group autoimmune PAP and hereditary PAP.

Autoimmune PAP (aPAP) is a disease that develops when a person’s immune system begins making proteins that attack GM-CSF. These proteins are called GM-CSF autoantibodies and large amounts of them prevent GM-CSF from helping alveolar macrophages remove excess surfactant. This results in surfactant accumulation and the development of PAP. Autoimmune PAP occurs mostly in adults but can occur in young children.

Hereditary PAP (hPAP) is a genetic disease that causes GM-CSF to not be recognized by alveolar macrophages. This prevents GM-CSF from helping alveolar macrophages remove excess surfactant. This results in surfactant accumulation and the development of PAP. Normally, GM-CSF is recognized by proteins on the surface of alveolar macrophages (and other cells) called GM-CSF receptors. Similar to the way a key fits into and turns a lock to open it, GM-CSF fits into these surface proteins and ‘opens’ or, rather, activates them. This causes alveolar macrophages to be able to remove excess surfactant. In hPAP, mutations occur in the genes that serve as blueprints for making GM-CSF receptors. The result is that when the blueprint containing ‘bad’ instructions is used, the GM-CSF receptors are abnormal and don’t recognize GM-CSF. Some mutations are so severe that the GM-CSF receptors aren’t even made. Hereditary PAP occurs mostly in children but can occur in adults.

Secondary PAP (sPAP) occurs when something reduces either the number of alveolar macrophages or reduces their ability to function to remove surfactant.

In either case, there are less alveolar macrophages inside alveoli to remove excess surfactant. This results in surfactant accumulation and the development of PAP. Secondary PAP can occur in diseases that affect the formation of blood cells. It can also occur after breathing in toxic dusts. Secondary PAP is more common in adults but can occur in children.

Disorders of surfactant production (DSP) are genetic diseases that cause abnormalities in proteins needed to make surfactant. This results in the production of abnormal surfactant. The disease that occurs depends on which gene is affected and exactly what mutation is present. Some mutations result in death in the first hour of life and some slowly scar the lungs over time and appear in children, adolescents, or adults.


What are the symptoms of PAP?

PAP usually causes a feeling of breathlessness (a feeling of being unable to breathe easily) that starts slowly and gets worse over time. Doctors refer to this as “progressive dyspnea of insidious onset”. Some patients develop a dry cough. Less commonly – in less than 5% of people with PAP, a frothy, whitish phlegm may accompany the cough. Rarely blood-streaked phlegm, chest pain, and fever may also be present, which indicate that infection is probably also present.


How is PAP diagnosed?

Evaluation of a person's symptoms and clinical tests cannot identify what disease is causing PAP. Chest x-rays reveal the presence of whitish, fluffy shadows throughout the lungs. Chest CT scans reveal areas of increased whitish shadows next to areas of normal appearing lung. Chest x-rays and CT scans can suggest but not prove that PAP syndrome is present. This is because other diseases can have a similar appearance. A lung biopsy can determine if PAP syndrome is present but can not identify which disease is causing PAP in any patient.

Blood tests identify the disease in most patients with PAP. Detection of GM-CSF autoantibodies in the blood is used to identify aPAP. Detection of genetic mutations in genes for GM-CSF receptors is used to identify hPAP. Secondary PAP is diagnosed on the history and clinical findings. Detection of genetic mutations in genes needed to make surfactant is used to identify DSP.


How common is PAP?

Current estimates suggest that 40,000 - 50,000 PAP patients exist worldwide.


What is the natural history of PAP?

Symptoms may improve spontaneously in a small percentage of patients. More commonly, symptoms persist for long periods of time or progress more rapidly.


What is the treatment for PAP?

The most common treatment for PAP is whole lung lavage, a procedure used to ‘wash’ surfactant out of the lung. This therapy is useful in aPAP, hPAP, and some types of sPAP but is not useful in DSP.


Future

Several potential treatments for PAP are in development and testing. Inhaled GM-CSF is an interesting and promising approach for aPAP. Pulmonary macrophage transplantation is a potential therapy that is in development for hPAP.

What is Hermansky-Pudlak Syndrome (HPS)?

Hermansky-Pudlak Syndrome (HPS) is a rare disease characterized by light coloring of the skin, hair, and eyes (oculocutaneous albinism) and bleeding problems due to abnormal platelet function. Some HPS patients develop scarring of the lungs called pulmonary fibrosis.


What is the cause of HPS?

Genetic mutations in genes related to cell function cause HPS.


What are the symptoms of HPS?

The most common symptoms of HPS are light coloring of the skin, blindness, the tendency to bleed easily, and development of lung problems in some subtypes of HPS. Individuals with HPS have decreased vision, which is frequently severe enough to be legally blind. Other vision related symptoms are nystagmus (involuntary side to side movement of the eyes), photophobia (light sensitivity), and strabismus (crossed eyes). Intestinal, kidney, and heart problems are less common.


How is HPS diagnosed?

Light colored skin, hair, and eyes are the first recognized features of HPS. The standard for HPS diagnosis is a specialized test on platelets called electron microscopy (EM). Genetic testing for HPS genes can also be useful.


How common is HPS?

HPS is most prevalent in Puerto Rico, where the frequency is estimated to be one in 1,800. It is suspected to be underdiagnosed. Current estimates suggest there are 10,000 - 20,000 HPS patients worldwide.


What is the natural history of HPS?

All individuals with HPS have some degree of vision problems and albinism, but the severity can vary. Bleeding problems can range from easy bruising to severe bleeding with surgery or injury. Colitis occurs in some individuals with HPS, and may be treated with a variety of medications. A lung problem, specifically pulmonary fibrosis, is the most serious complication of HPS for adults with certain subtypes of HPS (HPS1, HPS2, and HPS4). Patients may have chronic cough and become short of breath. There is no proven effective treatment for HPS. Lung transplantation has helped a small number of patients.


What is the treatment for HPS?

HPS patients that are blind should be provided with vision services, minimize sun exposure through use of sunscreen and also protective clothing, and obtain regular skin exams due to skin cancer risk.

HPS patients that bleed easily should avoid taking aspirin, ibuprofen or other NSAIDs, and anticoagulants. Use of a medical alert product such as a bracelet or necklace is strongly advised. There are no formal studies, but expert opinion has been to recommend consideration of pre-medication with desmopressin for procedures likely to cause minor bleeding. For more severe bleeding or procedures, a platelet transfusion may be required. Use of a single donor for platelet transfusion is advised whenever possible, as some HPS patients have unfortunately developed significant sensitization that can impact lung transplant considerations in the future.

HPS patients with colitis are managed similarly to Crohn’s disease and has been successfully treated with anti-TNF therapy. Surgical resection has been performed as a last resort in some cases.

For HPS patients with pulmonary fibrosis, supplemental oxygen and other symptomatic care should be provided, if needed. There is no established role for the use of steroids or cytotoxic agents. Referral for lung transplantation should be considered, including time for pre-transplant planning with a hematologist regarding management of platelet dysfunction and bleeding risk. Emerging therapies for Idiopathic Pulmonary Fibrosis (IPF) may also have a role in treating HPS patients who have patterns of pulmonary fibrosis similar to that seen in IPF.

Additional information and patient support is available through the HPS Network (https://www.hpsnetwork.org/).

What is Birt-Hogg-Dubé syndrome (BHD)?

Birt-Hogg-Dubé syndrome (BHD) is a rare disease characterized by the development of hair follicle tumors (fibrofolliculomas), kidney tumors, and lung cysts (air-filled pockets inside the lung tissue). The lung cysts can rupture, thus putting patients with BHD at an increased risk of developing a pneumothorax (lung collapse due to air leakage around the lung).


What causes BHD?

BHD is caused by mutations in a tumor suppressor gene called Folliculin (FLCN). Mutations in FLCN render the patients more susceptible to the development of tumors. Disease causing mutations in BHD are germline mutations (they are present in every cell of the body), and thus BHD is an inheritable disease. BHD is inherited in an autosomal dominant fashion, i.e only one abnormal gene from a parent can pass on the disease to the children.


What are the symptoms of BHD?

The spectrum of symptoms in BHD varies considerably from patient to patient. Some patients are asymptomatic, while others seek medical attention for abnormal skin lesions, most commonly seen on the face. The hair follicle tumors (fibrofolliculomas) are seen in greater than 80% of adult patients with BHD.

Another common presentation for patients with BHD is the development of a pneumothorax (lung collapse due to air leakage around the lung). Greater than 80% of patients with BHD have lung cysts that are prone to rupture, thus putting patients with BHD at a very high risk for the development of a pneumothorax. Common symptoms that might be seen with a pneumothorax are sudden onset shortness of breath and chest pain. Typically the chest pain is located on one side of the chest, and is worse with deep breathing. 


How is BHD diagnosed?

Often patients with BHD are diagnosed after an episode of pneumothorax. The lung cysts in BHD have a characteristic appearance, and an expert radiologist can identify BHD with a high degree of certainty based on a review of the chest CT scan. However, due to lack of knowledge about this disease, the diagnosis is frequently missed and patients are commonly labeled to have emphysema or some other cystic lung disease.

There are two ways to confirm the diagnosis of BHD:

  1. Biopsy of a skin lesion to document the presence of characteristic hair follicle tumors seen in BHD.
  2. Genetic testing to look for the presence of disease causing FLCN mutations.

With a combination of both these methods, the diagnosis of BHD can be made with certainty in greater than 90% of patients.


How common is BHD?

The exact prevalence of BHD is unknown. Current estimates suggest that there are between 10,000 – 20,000 patients with BHD worldwide. These numbers are likely an underestimate.


What is the natural history of BHD?

Almost all patients with BHD have hair follicle tumors and lung cysts. The hair follicle tumors are benign growths and don’t pose a major health hazard. Lung cysts frequently lead to the development of pneumothoraces. Approximately one-third of patients with BHD will experience at least one pneumothorax in their lifetime. Following a sentinel pneumothorax, there is a very high chance of developing recurrent pneumothoraces (75% rate of recurrence). On average, patients with BHD experience greater than 2 episodes of pneumothoraces in their lifetime. However, despite the frequent pneumothoraces, lung function in patients with BHD is relatively well preserved.

Patients with BHD are also at a higher risk for developing kidney tumors. Kidney tumors are typically seen in later in life as compared to the skin and lung manifestations. The average age of development of kidney tumors in BHD is 50 years, while skin and lung findings are commonly seen in the early 30’s. Kidney tumors in BHD can be of multiple types, and can be seen at more than one location, and often present on both kidneys. In general, these tumors tend to be slow growing and reports of spread to other organs (metastasis) are uncommon.


What is the treatment for BHD?

The skin lesions in BHD, while benign, can occasionally be disfiguring, causing significant psychosocial burden. Local destructive techniques such as laser and/or excision can be tried for management of skin lesions. However, these techniques are limited by a very high rate of recurrence of the skin lesions. Patients should seek expert opinion from a dermatologist familiar with BHD in order to choose individual treatment options after discussing the potential risks and benefits.

Pneumothorax prevention and treatment are the main principles of pulmonary management in patients with BHD. All patients with BHD should get a CT scan of their chest to estimate the degree of cyst burden in their lungs. Smoking is a known risk factor for developing a pneumothorax in the general population. Patients with BHD should quit smoking. Because of the high chance of developing a future pneumothorax, patients with BHD should undergo interventions such as pleurodesis aimed to prevent/decrease the rates of future pneumothoraces after their first episode of pneumothorax.

Kidney tumors are the most life threatening manifestation of BHD. Patients with BHD should undergo routine screening for kidney cancers. Screening is typically started after the age of 20 years. While the exact modality of screening (ultrasound, CT scan, MRI) is not known, MRI may be the better option as it does not miss small lesions (a problem with ultrasound), and it does not expose patients to radiation (a problem with CT scan). Surgery is recommended if a kidney tumor reaches greater than 3cms in size.


Future

The reasons for formation of lung cysts in patients with BHD need to be better understood. With increased knowledge about the genetics and tumor-formation in BHD, there is hope that effective targeted therapies aimed to stop tumor progression can be developed for patients with BHD.

What is Pulmonary Langerhans Cell Histiocytosis (PLCH)?

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare disease characterized by the formation of multiple lung cysts (air-filled pockets inside the lung tissue). PLCH is seen most commonly in young to middle aged patients. The cysts can progress over time leading to a gradual decline in lung function.


What causes PLCH?

Approximately 90% of patients with PLCH either smoke cigarettes or have a history of exposure to substantial second-hand smoke. It is believed that exposure to cigarette smoke causes activation and accumulation of the Langerhans cell around the airways. Langerhans cells are specialized cells designed to regulate the immunity around the airway lining. Activation and accumulation of Langerhans cells invites other immune mediating cells to the airway and lung tissue leading to formation of cellular nodules. These nodules can damage the lung tissue over time and lead to formation of lung cysts.

In addition to the role of cigarette smoke, there may also be a subset of patients where PLCH is caused by underlying genetic mutations. Mutations in the BRAF gene have recently been linked to the development of PLCH. BRAF mutations are commonly known to cause cancers such as melanoma, and a variety of other cancers in humans. Presence of BRAF mutations suggests that at least a proportion of PLCH is a low-grade cancer rather than just a cigarette smoke induced disorder.


What are the symptoms of PLCH?

The spectrum of symptoms in PLCH varies considerably from patient to patient. The majority of the patients with PLCH presents with non-specific symptoms of shortness of breath on exertion, and cough. However, some patients are asymptomatic and are found incidentally on chest imaging performed for other unrelated reasons. Weight loss and fever may be seen in 20% of patients with PLCH. Approximately 15% of patients with PLCH may present with a pneumothorax (lung collapse due to leakage of air around the lungs). The common symptoms of a pneumothorax are sudden onset chest pain and shortness of breath, typically more on one side. The chest pain in case of a pneumothorax is worse with deep breathing. A small minority of patients may have disease spread outside the chest, typically with bone involvement suggested by bone pain and/or identification of bony lesions on imaging.


How is PLCH diagnosed?

The most important diagnostic test in patients with suspected PLCH is a high-resolution CT scan of the chest. Patients with PLCH have a typical appearance of the cysts and/or nodules on high-resolution chest CT. An expert radiologist can identify PLCH with a high degree of certainty based on chest CT alone. Some patients may need a lung biopsy if findings on chest CT are not diagnostic.


How common is PLCH?

The exact prevalence of PLCH is unknown. Current estimates suggest that there are between 40,000 – 50,000 patients with PLCH worldwide. These numbers are likely an underestimate.


What is the natural history of PLCH?

The natural history of PLCH is variable. Some patients have an excellent prognosis, while others progress at a rapid rate. In general, PLCH is a progressive disease and leads to a gradual decline in lung function over time. Average survival times of approximately 12-13 years after diagnosis have been reported in uncontrolled studies. Ongoing cigarette smoking is associated with a worse prognosis, and can accelerate the loss of lung function.

Patients with PLCH are at a higher risk of developing recurrent episodes of pneumothoraces (lung collapse). Following an episode of pneumothorax, there is a 60% chance that patients with PLCH will experience another pneumothorax.


What is the treatment for PLCH?

Cessation of cigarette smoking is key to the management of PLCH. Smoking cessation may lead to disease stabilization, and even regression, in patients with PLCH. Treatment options in patients who continue to progress after successful smoking cessation are limited and not well studied. Because of the high risk of recurrence, patients with PLCH who develop a pneumothorax should undergo procedures such as pleurodesis in order to prevent/reduce the risk of future pneumothoraces.


Future

The demonstration of genetic mutations in patients with PLCH has led to a paradigm shift in our thinking towards PLCH. The genetic basis of PLCH needs to be better established. With detection of underlying mutations, there is hope that patients with PLCH can someday receive effective, targeted therapies aimed at their specific disease causing mutations.

What is Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH)?

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a lung disease which often presents with symptoms of cough and shortness of breath. The chest radiograph may be normal or demonstrate hyperinflation, and the chest computed tomography scan often shows a mosaic pattern of light and dark regions with scattered nodules. The pathological definition published by the World Health Organization is “a generalized proliferation of scattered single cells, small nodules (neuroendocrine bodies), or linear proliferations of pulmonary neuroendocrine (PNE) cells that may be confined to the bronchial and bronchiolar epithelium.”


What causes DIPNECH?

The overgrowth of pulmonary neuroendocrine (NE) cells likely contributes to the manifestations of the disease, but the mechanism driving pathogenesis is unknown.


What are the symptoms of DIPNECH?

The most common symptoms include: chronic cough, shortness of breath or labored breathing when exercising or exerting one’s self, wheezing (less frequent), and coughing up blood (infrequent). About 20% of DIPNECH patients are symptom free at the time they first present.


How is DIPNECH diagnosed?

The diagnosis of DIPNECH is frequently delayed because respiratory symptoms are nonspecific and often attributed to other lung diseases. DIPNECH is a female-predominant lung disease manifested by shortness of breath and cough, airflow obstruction, and nodules on high-resolution computed tomography (HRCT) imaging. The diagnosis can be strongly suspected clinically based on nodules and a mosaic pattern of dense and lucent areas on HRCT. A definitive diagnosis typically requires video assisted surgical biopsy. A serum biomarker, chromogranin A, is sometimes found in the blood of patients with DIPNECH.


How common is DIPNECH?

The prevalence of DIPNECH is not known. As of July 2017, nearly 200 cases have been reported in the medical literature. However, with an increase in recognition of this disease by radiologists and pulmonologists, the number of cases identified has been increasing.


What is the natural history of DIPNECH?

The lung disease tends to be slowly progressive, but given enough time can lead to significant disability and need for supplemental oxygen therapy. There have been reports of lung transplantation for end-stage DIPNECH.


What is the treatment for DIPNECH?

To date there have been no clinical trials to determine effective treatment for this disease. Some patients have been treated with somatostatin analogs. Although the cough associated with DIPNECH has been reported to diminish on this treatment, improvement in pulmonary function has not been clearly demonstrated. There are also reports of symptomatic benefit from treatment with long- and short-acting beta agonists. Although steroids (both oral and inhaled) have been used in the setting of DIPNECH, there is no clear consensus on the effectiveness of this treatment.


Future

There is interested in the use of mTOR inhibitors in DIPNECH, based on immunohistochemical staining which reveals upregulation of that pathway. Clinical trials in patients with DIPNECH are difficult because the disease is rare and patients are geographically dispersed. The RLDC may provide a mechanism to conduct trials in the future.