Neurofibromatosis

Podcast

Author and Contributing Experts to this Guide include:

What is Neurofibromatosis?

Neurofibromatosis (NF) is a genetic disorder that affects the nervous system. It can affect the body in many ways, but the primary concern with this condition is that it can cause peripheral nerve tumors and disrupt how nerve cells form and grow.

Benign tumors, called neurofibromas, can develop along the linings of the nerves under a person's skin or in deeper areas of the body. 

These tumors usually are benign, however, they can sometimes be cancerous. This disorder can lead to many deformities, which can affect patients on a day-to-day basis.

NF is caused by a genetic difference in one of four genes: NF1, NF2, SMARCB1, or LZTR1. It can either be inherited, meaning passed down from a parent, or the genetic difference might occur for the first time in the patient.

NF is a lifelong disorder that equally affects both males and females and people of all ethnicities. 

“It is a complicated condition because NF affects many systems of the body and is notoriously unpredictable,” said Bruce Korf, a medical geneticist and Dean for Genomic Medicine and Chief Genomics Officer at the University of Alabama at Birmingham.

Korf is also recognized for his work in rare disease diagnosis and management, with a longstanding special interest in neurofibromatosis.

"NF can range from a pretty mild condition that doesn't have any major medical complications to something that can be very serious, disfiguring, and in a few cases, potentially even life-threatening. From one person to another, even in the same family, it's really difficult to predict how it's going to behave," he added. 

There are three types of neurofibromatosis:

Neurofibromatosis Type 1 (NF1): This is the most common type of NF. It is caused by a harmful difference in a gene called NF1. It affects approximately 1 in 3,000 people throughout the world.

Individuals with this condition will have skin differences, and sometimes bone deformities. It usually starts in childhood, but symptoms are sometimes present at birth.

Neurofibromatosis Type 2 (NF2): This is a less common type of NF. It is caused by a harmful difference in a gene called NF2. It affects approximately 1 in every 25,000 people in the world. This type can cause hearing loss, ringing in the ears, and poor balance. These symptoms generally start in the teenage years.

Schwannomatosis: This type is the rarest type of NF, affecting 1 out of every 40,000 people in the world. It is caused by a harmful difference in either LZTR1 or SMARCB1. It causes intense pain due to tumor growth on the spine and peripheral nerves.

Neurofibromatosis is also sometimes referred to as:

  • Peripheral Neurofibromatosis
  • Recklinghausen Nerve Disease
  • Von Recklinghausen Disease
  • Von Recklinghausen Neurofibromatosis

Neurofibromatosis Symptoms

The symptoms and severity of neurofibromatosis are different for each person and will also depend on which type of NF a person has.

“Most patients with neurofibromatosis will have some clinical problems. Those can range from 10 to 15 percent of the patients that generally have mild symptoms where they have enough that we can look at them and say, 'Yes, you have this condition but don't need a lot of interventions." said Rob Hoskin, an associate professor of clinical pediatrics at Cincinnati Children's Hospital Medical Center in the University of Cincinnati College of Medicine.

“Another 10 to 15 percent will have life-threatening or severely impairing complications. The rest of the people with NF will have something in between. 

“NF has a pretty big spectrum. It's well known for being highly variable, even family members with the same mutation will have very different manifestations.” 

NF1 Symptoms 

Café Au Lait spots: These are light brown spots that are flat on the skin. They’re not harmful but can cause the patient with the spots to have body image impairment when they appear in visible places such as the face.

"The most common initial sign, which can often be seen in infancy, is some skin lesions that look like giant freckles. They're called cafe au lait spots. Cafe au lait means coffee with milk, and the spots are the color of coffee with milk, and they're a centimeter or larger, typically, in diameter, and they just look like big freckles," said Hoskin.

"In and of themselves, the cafe au lait spots don't cause problems, but if you have six or more of them, that is a reason to wonder, could this be Neurofibromatosis Type 1."

Other skin findings can include freckling in the armpit or groin areas. 

Neurofibromas: These are the typical NF1 lumps that appear under and on the skin. These bumps are generally not medical issues. However, they can cause pain, itching, and body image impairment to those who have them.

Some people only present with a few of these bumps in number where others can have hundreds on their bodies. As people with this condition age, they tend to develop more neurofibromas.

"The small ones that are usually in the skin called cutaneous neurofibromas are marble-sized, sometimes even smaller than that, sometimes a little bigger. They are typically soft and not usually going to be associated with major health problems. Still, they can itch or be tender or otherwise uncomfortable, they can cause cosmetic problems," Hoskin added.

Plexiform neurofibromas: These are a much less common type of neurofibroma and occur in approximately 25% of people with NF1. They can grow very large and cause complications, such as putting pressure on nerves and organs.

In about 10% of this type of neurofibroma, it becomes malignant. 

"These larger neurofibromas infiltrate into the surrounding tissue. They can then grow in any part of your body, and as they get bigger, they can compress the surrounding organs and lead to some pretty serious complications depending on where they are," said Hoskin.

Cognitive challenges: Intelligence levels with those with NF1 are typically within the normal range. However, children with NF1 may need more help in school.

In approximately 50% of all NF1 cases, learning difficulties occur in children.

Optic pathway tumors: The nerve behind the eye is called the optic nerve. In NF1, tumors called optic glioma might occur and develop in the cells that surround the optic nerve.

Approximately 15% of those with NF1 will develop this type of tumor. 

Children under the age of six years are at the highest risk for developing an optic glioma. The first signs or symptoms generally occur at around 18-months-old.

Many times, optic gliomas do not cause symptoms. However, they can occasionally affect vision and require chemotherapy to treat.

Other eye findings can include Irish Lisch nodules which are tan/brown colored pigments in the colored part of the eye. Sometimes the eye can also have freckles. 

Delayed or early puberty: Although most individuals with NF1 will begin puberty at a normal age, some may experience precocious (early) or delayed puberty.

Small stature: This is another symptom of NF1. Approximately 30% of those with NF1 will have a small stature and need to be treated with growth hormone.

High blood pressure: This is a serious complication for a small fraction of people with NF1, which is why people with NF1 should have their blood pressure checked regularly.

Bone issues: Approximately 5% of patients experience curvature of the lower leg bone or tibia. This leads to bones that fracture easily and don’t heal well. Also, as many as 20% of patients develop a curvature in the spine or scoliosis.

NF2 Symptoms 

Hearing and balance issues: NF2 is usually characterized by hearing and balance difficulties. This is due to tumor growth on the eighth cranial nerves (or the nerves leading to the ears).

Vestibular schwannomas: These are the hallmark tumors in patients with NF2. These are benign and can cause hearing loss in one or both of the ears. Vestibular schwannomas are abnormal Schwann cells. These cells give lining and insulation to the nerves and are needed to conduct information.

Meningiomas: These are benign, contained tumors on the lining of the brain and spinal cord. Approximately 80% of people with NF2 will develop meningiomas in their lifetime. These can cause severe symptoms such as headaches, seizures, and numbness. However, most do not cause symptoms until they are noticeable in size. 

Ependymomas: These tumors develop in about 20% of people with NF2. They are located on the cells lining the ventricles of the brain and the center of the spinal cord.

Nerve damage: Since all of the nerves in the body are associated with different functions, damage can happen to the senses, muscles, and organs resulting in the following symptoms:

  • Ringing in the ears (tinnitus)
  • Problems with balance
  • Facial weakness
  • Vision loss (Lisch nodules appearing on the iris)
  • Brain and cranial nerve damage
  • Hearing loss
  • Swallowing difficulties
  • Seizures
  • Loss of balance and mobility due to spinal tumors
  • Peripheral neuropathy
  • Pain
  • Muscle wasting
  • Persistent facial palsy
  • Hand/foot drop

Schwannomatosis Symptoms 

Tumors, called schwannomas, grow most commonly on peripheral and spinal nerves. They can cause localized or diffused pain that can range anywhere from mild to severe.

However, sometimes they do not cause pain and are instead simply a mass.

Unlike Neurofibromas in NF1, these tumors grow deep within the patient's body resulting in pain when the tumor presses a nerve against a bony structure. 

Other symptoms related to schwannomatosis include but are not limited to:

  • Numbness or tingling
  • Vision changes
  • Weakness, including facial weakness
  • Headaches
  • Bowel dysfunction or difficulty urinating

Causes of Neurofibromatosis 

In some cases, NF is inherited from a person’s parents. Other times, NF is not inherited from parents, but is instead due to a brand new genetic difference occurring in the sperm or egg cells.

NFI and NF2 are caused by harmful differences in two different genes that can be inherited by a patient’s parents. NF1 is caused by harmful differences in a gene called NF1 which is located on chromosome 17, and NF2 is due to harmful differences in a gene called NF2 which is located on chromosome 22. NF does not skip generations.

The *NF1* gene regulates the production of neurofibromin, a protein that functions to suppress tumor development. When the gene is not working correctly, it can lead to a nonfunctional version of neurofibromin, or a reduced expression of neurofibromin, leading to disrupted cellular growth and division which can lead to tumor development. 

In some cases, the entire NF1 gene may be missing (and in some cases, material from other adjacent genes), which helps to explain why there is a wide variation in symptoms from patient to patient.

The NF2 gene is genetically distinct from the NF1 gene. It is characterized by benign auditory nerve tumors called vestibular schwannomas, and tumors in other parts of the body. This produces problems with balance, ringing in the ear, and a loss of hearing.

Both NF1 and NF2 are considered to have an autosomal dominant inheritance pattern. Everyone has two copies of all of their genes, one set from their mother and one set from their father.

Individuals with NF1 or NF2 only need one copy of the respective gene to not be functioning properly to have the condition. In about half of the cases, the non-working gene is inherited from a parent.

The other half of the cases are a result of a new genetic change that occurs in people with no family history of the condition.

In other words, each child has a 50/50 chance of developing NF if one parent has NF. If a parent has a non-working copy of the NF1, then the child has a 50/50 chance of inheriting the same non-working copy and having Neurofibromatosis Type 1.

Likewise, if the parent has a non-working copy of NF2 gene, then the child has a 50/50 chance of inheriting the same non-working copy and having Neurofibromatosis Type 2.

The NF1 gene is large and has one of the highest known mutation rates (1:10,000) for any human gene. Research is still ongoing to determine why the rate is so high, but speculation suggests that it may be due to how large the gene is, which can lead to a greater chance of random error during cellular growth.

Genetic counseling is recommended for anyone who has a family history of NF.

Possible Complications

Neurofibromatosis can lead to complications, including:

  • Attention deficit hyperactivity disorder (ADHD)
  • Blindness caused by a tumor in an optic nerve (optic glioma)
  • Breaks in the leg bones that do not heal well
  • Cancerous tumors
  • Loss of nerve function due to long-term pressure by tumors
  • High blood pressure due to pheochromocytoma or renal artery stenosis
  • Regrowth of NF tumors
  • Scoliosis or curvature of the spine
  • Multiple tumors on the face, skin, and other exposed areas

Diagnosis of Neurofibromatosis

Diagnostic criteria for NF is different depending on the type.

Genetic testing is available in most instances through a blood test, but it is not typically performed to diagnose NF.

“Sometimes having the genetic test result can be helpful. For example, if somebody is missing the whole gene, and you have a whole gene deletion of the NF1 gene, the disease tends to be more severe, and the learning disabilities more severe. When that’s the case, we will change some of the management recommendations for that,” said Hoskin.

The primary diagnostics used are a review of the family history and physical examination of the patient when they start to exhibit symptoms.

“There are well-developed diagnostic criteria for neurofibromatosis. We look for seven things on a clinical evaluation. That includes the cafe au lait spots, freckling in the armpits and the groin area, two or more cutaneous neurofibromas or one plexiform neurofibroma, bowing of the long bones, Lisch nodules of the eyes, presence of an optic glioma or a first-degree relative, meaning a sibling or a parent who has neurofibromatosis," said Hoskin. 

The diagnosis in NF1 is primarily based on a medical examination. For a patient to be diagnosed with NF1, they must meet TWO of the following specific criteria:

  • Six or more café au lait spots that are 5 mm or greater in prepubertal children or 15 mm or greater in post-pubertal adolescents or adults
  • Two or more neurofibromas of any kind, or one or more plexiform neurofibromas
  • Freckling on the underarm
  • Optic glioma
  • Two or more Lisch nodules, which are benign colored spots in the eye
  • A distinctive bony lesion: dysplasia or abnormal growth of the sphenoid bone behind the eye, or dysplasia of long bones, many times in the lower leg
  • Have a close relative (parent, sibling, or child) with NF1

An NF2 diagnosis is made when ONE of the following collections of signs and symptoms occur:

  • Bilateral vestibular schwannomas (on both ears)
  • A first degree relative with NF2, plus a unilateral (on one ear) vestibular schwannoma

Or, any TWO of the following:

  • Meningioma
  • Juvenile cataracts
  • Glioma
  • Schwannoma
  • Neurofibroma (or unilateral vestibular schwannoma)
  • Multiple meningiomas (two or more) and unilateral vestibular schwannoma

A schwannomatosis diagnosis is made when a patient meets ONE of the following criteria:

  • Two or more non-intradermal schwannomas, one with the confirmation of pathology, including no bilateral vestibular schwannoma by high-quality MRI.
  • Confirmation of one pathological schwannoma or intracranial meningioma and a first-degree relative like a parent or a sibling that has been affected by NF.

Or, in the case that two or more non-intradermal tumors occur, but none has been pathologically proven to be a schwannoma, it will be considered a possible diagnosis. With this potential diagnosis, chronic pain with the development of tumors increases the likelihood of schwannomatosis.

Prenatal Diagnosis for Neurofibromatosis 

Prenatal genetic testing is available to diagnose NF. It can either be done through amniocentesis or chorionic villus sampling to detect a non-working copy of NF1.

Prenatal testing is also available for NF2, but only about 65% of those tested receive an accurate diagnosis. In order to undergo prenatal diagnosis, there needs to be a known familial genetic difference in either NF1 or NF2.

If there is a known genetic difference in the family in either LZTR1 or SMARCB1 which causes Schwannomatosis, then prenatal diagnosis or pre-implantation diagnosis can be performed to determine if the baby will carry the same difference.

Who Should Be Screened for Neurofibromatosis?

Any person who shows outward signs and symptoms of NF (tumors, hearing loss, balance issues, or cognitive delays) should be screened for the condition.

Also, any person who has immediate relatives with NF should be screened regularly starting in childhood.

Those who have first degree relatives (parents, siblings, children) with neurofibromatosis should be screened throughout adolescence into adulthood to make sure they do not show any of the signs or symptoms of the disease. Any individual that has pain, abnormal lesions, or tumors on the skin, hearing loss, balance complications, or cognitive delays should consult a physician for a formal screening.

There is not always consensus on screening and testing, however.

“Some things are controversial. Not everybody agrees about whether to do brain MRIs in young children to look for optic gliomas. Some doctors say, ‘Yes, we should screen with MRIs." And there's another group that says, "No, we should have annual eye evaluations, but we shouldn't do any imaging studies unless we have a hint of a problem,’” commented Hoskin.

Neurofibromatosis Treatment Options

“Earlier treatment helps, even for learning problems, recognizing that there are needs early and putting in plans to address those makes a big difference in the outcomes for the patients,” explained Hoskin.

“My big message for most genetic conditions, including NF, is to find your diagnosis and then talk to people about it, learn about it, and face the disorder because there are things that can be done and they do make a difference in the long-term outcome.

"For young children, we need to get eye exams; we need to monitor blood pressure, even starting in childhood. We need to look for the optic gliomas, the neurofibromas, and other manifestations and then find ways of addressing those," he added.

Gene therapy is currently being researched to treat NF, but it is not currently available for patients. Instead, because there is no cure, treatment focuses on treating various symptoms.

Because NF can affect so many areas of the body, a wide variety of professionals will probably be necessary to render effective treatment. These professionals can include:

  • Cardiologists
  • Dermatologists
  • Genetic Counselors
  • Neurologists
  • Orthopedic Specialists
  • Oncologists
  • Ophthalmologists
  • Pediatric Specialists
  • Psychologists

In addition to these specialists, when a patient is diagnosed with NF2, it is also advisable to add an ear, nose, and throat specialist (otolaryngologist) to better monitor hearing loss and bilateral vestibular schwannomas.

Patients with NF may have surgeries to remove disfiguring tumors, but this depends on their size and location. In some cases, laser surgery or electrocautery may be a course of treatment, especially for smaller skin abnormalities.

In some instances, chemotherapy or radiation therapy may also be employed, but this is less common.

“Historically, for tumors, the only thing we could do was surgery. But these tumors grow on nerves, and so you have to be careful not to damage the nerve if possible. They also have lots of blood vessels and other things in them, so doing surgery on the tumors was quite intimidating and had lots of potential complications.

“We still do use surgery for some things, but now there are medications that can shrink the tumors or, in some cases, prevent them from growing. We don't have any that can prevent neurofibromas from forming in the first place at this point, but certain medications can help to decrease the progressive nature of the disease,” said Hoskin.

That’s a sentiment echoed by medical geneticist, Bruce Korf. 

“I think the most exciting area is there's been a fair amount of progress in the development of therapeutics. And we do now have a family of drugs collectively called MEK inhibitors.

“They have been shown in various clinical trials to have some significant effectiveness in helping to shrink plexiform neurofibromas. So, there are drugs, some of them are available either for off-label use or under some circumstances for compassionate use.”

However, the medical community is still waiting for an FDA-approved drug to treat NF.

“We’re hopeful that there will be an FDA-approved drug at some point soon. We're not quite there yet, but that seems to be the direction things are moving in.

“It has changed our way of thinking about the management of NF. In the past, some of these tumors were deemed inoperable and there was little you could do other than trying to remove some of the excess bulk if there were major symptoms. But that was a pretty unsatisfying approach and sometimes just not possible,” added Korf.

Orthopedic devices may also be prescribed depending on symptoms. For example, a patient who develops scoliosis may require a back brace to slow the progression.

Monitoring the progression of NF is critical to being responsive. Annual physical exams are highly recommended, including blood pressure and eye exam screenings.

Advanced imaging such as an MRI or PET scan may also be used to monitor internal tumors.

A highly recommended part of any treatment should include genetic counseling for a patient and their families.

Prognosis of Neurofibromatosis

Because each case of NF is different, the prognosis will vary from patient to patient. It is a progressive disease, so symptoms will get worse over time.

Although no cure exists, if there are no complications, the life expectancy for someone with NF1 is close to normal. Also, people can generally live a normal life, as defined by their particular symptoms.

Because NF2 and Schwannomatosis are so rare, there are few documented studies to determine if and how NF will affect a person’s lifespan.

Body image impairment can be an issue for those people with NF who are treated differently in public because they may have dozens or hundreds of tumors on their skin.

In some cases, when severe tumors develop, it can result in life-threatening or fatal complications.

Because Neurofibromatosis can be complicated in so many ways, finding a strong support group can provide valuable resources to ease the daily issues associated with this condition.

“The biggest support group nationally is the Children's Tumor Foundation. And even though it sounds like it might be a generalized cancer support group, it's focused primarily on Neurofibromatosis,” said Hoskin.

“Most cities will have some physicians who have a particular interest in neurofibromatosis. So, you can also just put in the name of the city you live in and Neurofibromatosis and look for where there is a specialized interest or where are the experts in that city,” he added.

Here are some other resources that focus on helping people with NF.

Resources

The National Organization for Rare Diseases lists the following resources for assistance with neurofibromatosis.

Children’s Tumor Foundation

370 Lexington Avenue

Suite 2100

New York, NY 10017

Phone: (212) 344-6633

Email: info@ctf.org

Website: http://www.ctf.org/

Neurofibromatosis Network

213 S. Wheaton Ave.

Wheaton, IL 60187

Phone: (630) 510-1115

Toll-free: (800) 942-6825

Email: admin@nfnetwork.org

Website: http://www.nfnetwork.org

Neurofibromatosis Northeast

9 Bedford Street

Burlington, MA 01803

Email: info@nfincne.org

Website: http://nfnortheast.org/

NORD’s Rare Cancer Coalition (RCC)

1779 Massachusetts Avenue NW

Ste 500

Washington, DC 20036

Phone: (202) 545-3971

Email: Membership@RareDiseases.org

Website: https://rarediseases.org/get-involved/rare-cancer-coalition/

RASopathies Network USA

244 Taos Road

Altadena, CA 91001-3953

Phone: (626) 676-7694

Email: info@rasopathiesnet.org

Website: http://www.rasopathiesnet.org

Other Organizations

BC Neurofibromatosis Foundation

Box 5339

Victoria, BC, V8R 6S4 Canada

Toll-free: (800) 385-2263

Email: info@bcnf.bc.ca

Website: http://www.bcnf.bc.ca

Cancer.Net

American Society of Clinical Oncology

2318 Mill Road Suite 800

Alexandria, VA 22314

Phone: (571) 483-1780

Toll-free: (888) 651-3038

Email: contactus@cancer.net

Website: http://www.cancer.net/

Children’s Hospital of Philadelphia Neurofibromatosis Program

The Children's Hospital of Philadelphia

3401 Civic Center Blvd

Philadelphia, PA 19104

Phone: (215) 590-7012

Toll-free: (800) 879-2467

Website: http://www.chop.edu/centers-programs/neurofibromatosis-program#.V6i7G1UrIdU

Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Phone: (301) 251-4925

Toll-free: (888) 205-2311

Website: http://rarediseases.info.nih.gov/GARD/

Let Them Hear Foundation

1900 University Avenue, Suite 101

East Palo Alto, CA 94303

Phone: (650) 462-3174

Email: info@letthemhear.org

Website: http://www.letthemhear.org

Massachusetts General Hospital Neurofibromatosis Clinic

15 Parkman St. 8th Floor, Room 835

Boston, MA 2114

Phone: (617) 724-7856

Email: SPlotkin@partners.org

Website: http://neurosurgery.mgh.harvard.edu/NFclinic/

Medical Home Portal

Dept. of Pediatrics

University of Utah

Salt Lake City, UT 84158

Phone: (801) 587-9978

Email: mindy.tueller@utah.edu

Website: http://www.medicalhomeportal.org

Neurofibromatosis Clinic at Texas Children’s Hospital

6701 Fannin Street, #1560

Houston, TX 77030

Phone: (832) 822-4280

Toll-free: (800) 364-5437

Email: plunkett@bcm.edu

Website: http://www.texaschildrens.org/departments/neurofibromatosis-clinic

NIH/National Institute of Neurological Disorders and Stroke

P.O. Box 5801

Bethesda, MD 20824

Phone: (301) 496-5751

Toll-free: (800) 352-9424

Website: http://www.ninds.nih.gov/

Rare Cancer Alliance

1649 North Pacana Way

Green Valley, AZ 85614 USA

Website: http://www.rare-cancer.org

Everything to know about Neurofibromatosis, from the experts.

Hear from the experts in our conversations on a rare genetic disease: Neurofibromatosis. We cover Neurofibromatosis diagnosis, new treatment options, and how to connect with the Neurofibromatosis community.

Experts in this episode include:

  • Robert J. Hopkin, MD, an associate professor of clinical pediatrics at Cincinnati Children's Hospital Medical Center, in the University of Cincinnati College of Medicine.
  • Dr. Bruce Korf, MD, PhD, a medical geneticist, director of the Heflin Center for Human Genetics and chairman of the Department of Genetics at the University of Alabama at Birmingham.
  • Emily Sites, LGC, a genetic counselor with a specialty focus in Neurofibromatosis, and coordinator of the Neurofibromatosis Clinic at at Nationwide Children's Hospital in Columbus, OH.
  • Annette Bakker, PhD, President of the Children's Tumor Foundation and Board Member at NYBIO.

More resources and information for you: raredisease.com/nf

Transcript

Nate: You're listening to the Rare Disease Connection production of Aspect Health and raredisease.com. There are roughly 7,000 rare diseases and estimates are that a rare disease affects nearly one in 10 Americans and hundreds of millions of people worldwide. And the genetic disorder we cover in this episode is actually relatively common. Neurofibromatosis type 1 occurs in one in 3,000-4,000 people worldwide. Nate: When you hear numbers like that, it's clear that rare diseases aren't so rare. It's impossible to know how many rare diseases go undiagnosed. If you or someone you love is affected by a rare disease, you likely have more questions than answers and that's why we're here. Rare Disease Connection and our additional resources on raredisease.com and yourdna.com brings together the people whose expertise can explain what you're facing, from diagnosis to prognosis, to treatment options, all the way to questions like who do I talk to? Where are the people who've been through this before? You'll find those answers here, from doctors, geneticists, academics, genetic counselors, patient organizations, other patients and their families, all within your reach. We're here to connect you. This is rare disease connection. Nate: Hey everyone, this is Nate cohost of Rare Disease Connection and a co-founder of Aspect Health. I'm excited to bring to you some recent conversations we've had with experts around the world about a very specific rare genetic disorder, neurofibromatosis. Before you listen, we know that hearing from these experts is only the beginning for you. That's why we've taken the information here and added additional resources, explanations, links, and references for you in a downloadable guide on neurofibromatosis that covers NF types 1, 2 and 3. You can get your free copy of that guide by going to raredisease.com/nf, that's raredisease.com/nf. Head there for so much more to help you on your journey to understanding this disorder. It will certainly help support you and your ongoing plan of action. Nate: So the experts are here so let's talk about NF. Our first conversation is with Dr. Robert Hopkin. He's an associate professor of clinical pediatrics at Cincinnati Children's Hospital Medical Center within the University of Cincinnati College of Medicine. The majority of Dr. Hopkin's time is spent in caring for patients with genetic disorders. He has participated in natural history studies on neurofibromatosis type 1 and several other genetic conditions. Rob Hopkin: I'm Rob Hopkin, I am a clinical geneticist. I have been practicing for about 25 years and I'm interested broadly in genetic diseases. I first came into this space with an interest in multiple malformation syndromes and have continued that and I'm also interested in lysosome or storage diseases. One of my big focuses is longitudinal follow-up and what can we do after we make a diagnosis that improves the life of the patient. Nate: Just to kick things off, setting a framework for how patient, family member, loved one who may have been diagnosed with NF, kind of what they're facing, what that first meeting looks like for you when they come into your office. Rob Hopkin: Neurofibromatosis is a relatively common rare disorder, if that makes any sense, and so we see it more than a lot of the other rare diseases, it's about one in 3,000 births. About half of the patients who have NF will have an affected family member, sometimes multiple affected family members. About half of them are a new mutation, meaning that nobody else in their family has ever had it and now you have somebody bringing up this disease out of the blue and that can be a little intimidating. Rob Hopkin: The most common initial sign, which can often be seen in infancy is some skin lesions that look like giant freckles. They're called the cafe au lait spots. Cafe au lait means coffee with milk and it's the color of coffee with milk and they're a centimeter or larger, typically, in diameter and they just look like big freckles. In and of themselves, the cafe au lait spots don't cause problems but if you have six or more of them, that is a reason to wonder, could this be neurofibromatosis type 1. Rob Hopkin: Then there are other... the other diagnostic criteria include freckles in places where you don't usually get freckles, specifically in the armpits and the groin area. That sign doesn't show up until people are few years old typically. And there's some subtle eye finding, there's something called lisch nodules that your ophthalmologist can look for that can help to confirm the diagnosis. Rob Hopkin: Now the things I've mentioned so far are hints that we should think about neurofibromatosis, but don't get into, well, why is this important? So the problems associated with neurofibromatosis type 1 include benign and potentially malignant tumors that will be seen in most of the patients. So the benign tumors that are most common are called neurofibromas and they can be on the skin or deeper in the tissues of the body. Rob Hopkin: The small ones that are usually in the skin called cutaneous neurofibromas are marble-sized, sometimes even smaller than that, sometimes a little bigger. They are soft typically and not usually going to be associated with major health problems but they can itch or be tender or otherwise uncomfortable, they can cause cosmetic problems. Rob Hopkin: Larger neurofibromas called plexiform neurofibromas infiltrate into the surrounding tissue. They can then grow in any part of your body and as they get bigger, they can compress the surrounding organs so they can lead to some pretty serious complications depending on where they are. Rob Hopkin: We also see bowing of the bones, particularly the bones in the lower legs, and that can lead to bones that fracture easily and that don't heal well, so those can be important things to find. There's also a brain tumor called an optic glioma that can occur usually in early childhood. Typically, first signs or the symptoms would be at 18 months to about five years old, for the optic glioma. Rob Hopkin: And obviously, when someone says brain tumor or any kind of tumor, that is kind of scary if you're the person who has the disorder or if it's your child who has the disorder. Some of the complications of neurofibromatosis can be quite severe, but a lot of people will live a normal life span. Rob Hopkin: Most patients with neurofibromatosis will have some clinical problems. Those can range from 10-15% of the patients will have generally mild symptoms where they have enough that we can look at them and say, "Yes, you have this condition but don't need a lot of interventions." Another 10 to 15% will have life-threatening or severely impairing complications, the rest of the people with NF will have something in between. So it has a pretty big spectrum, it's well known for being highly variable, even family members with the same mutation will have very different manifestations. Nate: With that amount of variability, I assume then there's so many different cases where you may need to form a team of certain specialists or see other specialists over time to keep an eye on things. Treatment options, I guess, would vary quite a bit then as well. Rob Hopkin: Yeah, treatment needs and treatment options are quite variable and there are growing numbers of treatment options. So historically for the tumors, the only thing we could do was surgery but these tumors grow on nerves and so you have to be careful not to damage the nerve if possible. And they have lots of blood vessels and other things in them so doing surgery on the tumors was quite intimidating and had lots of potential complications. Rob Hopkin: We still do use surgery for some things, but now there are medications that are able to shrink the tumors or in some cases prevent them from growing. We don't have any that can prevent neurofibromas from forming in the first place at this point, but there are certainly medications that can help to decrease the progressive nature of the disease. Rob Hopkin: There are also some manifestations that aren't related to tumors, so about 3/4 of patients will have learning disabilities that are significant enough that they need some modifications of their educational plan. There's an increased risk for hypertension and so there are lots of areas of the body and lots of different kinds of problems that can be seen. Nate: As you've described the symptoms and diagnosis, it doesn't sound like genetic testing is required to give a diagnosis of neurofibromatosis, but you can correct me if I'm wrong. And then I also wanted to ask, is there prenatal testing that can be done to see if a fetus has the disease? Rob Hopkin: So there are pretty well-developed diagnostic criteria for neurofibromatosis. There's seven things that we look for on a clinical evaluation. So we've mentioned several of them, the cafe au lait spots, freckling in the armpits and the groin area, two or more cutaneous neurofibromas or one plexiform neurofibroma, bowing of the long bones, the lisch nodules of the eyes, presence of an optic glioma or a first degree relative, meaning a sibling or a parent who has neurofibromatosis. Rob Hopkin: You look for those seven things, if you have two of those, then you have neurofibromatosis. And in that case, genetic testing isn't needed to establish the diagnosis. However, sometimes having the genetic test result can be helpful. So for example, if somebody is missing the whole gene, you have a whole gene deletion of the NF1 gene, the disease tends to be more severe and the learning disabilities more severe so we would change some of the management recommendations for that. Rob Hopkin: And there are some... a few mutations that have a milder phenotype. And we know because we've seen them enough times that if you have this particular mutation you are less likely to have the life-threatening complications. And that's kind of nice to know if you're one of those people. There's still a fair amount of variability even for people with the same mutation so we have... there's some protocols that have been made for what kinds of assessments to do. Rob Hopkin: And there's some things that are controversial, not everybody agrees about whether to do brain MRIs in young children to look for optic gliomas for example. So there's a group that says, "Yes, we should screen with MRIs." And there's another group that says, "No, we should have annual eye evaluations but we shouldn't do any imaging studies unless we have a hint of a problem." And I don't know what it will take to resolve those controversies. Nate: And I know that just hearing you talk about NF and all this information, it'll be so helpful for someone who has received that diagnosis or is trying to learn about the disease because a loved one or a family member, so it's come up and they're curious. I also know that patient groups, support organizations play a big role in many rare disease communities, genetic disorder communities. What do you know about the ones related to NF and where do you suggest people turn for more information? Rob Hopkin: So the biggest support group nationally is the Children's Tumor Foundation. And even though it sounds like it might be a generalized cancer support group, it's really focused primarily on neurofibromatosis. There are some other places that you can go and there is Neurofibromatosis Inc. But you can go online and search for NF1 or neurofibromatosis and there are lots of resources available. Some of it is written specifically for patients, some of it is written for educators or for physicians, so lots of options. Most cities will have some physicians who have a particular interest in neurofibromatosis. So you can also just put in the name of the city you live in and neurofibromatosis and look for where is there a specialized interest or where are the experts in that city. Nate: Well, I know there's a couple of different types of this disease, it's also a very common relative to some other rare genetic disorders. What is the most common misconception, the one thing that you feel like you often have to overcome when someone comes in and is first heard of this disease, the one thing that you wish folks might hear about NF, if they're listening to this conversation that may be an obstacle or a misconception? Rob Hopkin: The most common misconception about rare genetic disease is people assume that there's not much you can do about it and that's just globally false in my mind. There's almost always something that can be done, but for some disorders, the ones that we have the most information on, there's a lot that can be done and for neurofibromatosis, that's certainly true. So young children, we need to get eye exams, we need to monitor blood pressure even starting in childhood, we need to look for the optic gliomas, the neurofibromas and other manifestations and then find ways of addressing those. Rob Hopkin: And earlier treatment helps, even for the learning problem, recognizing that there are needs early and putting in plans to address those makes a big difference in the outcomes for the patients. So my big message for most genetic conditions, including NF1, is find your diagnosis and then talk to people about it, learn about it, face the disorder because there are things that can be done and they do make a difference in the long-term outcome. Nate: Thanks to Dr. Hopkin. Next, we spoke with Dr. Bruce Korf, Dr. Korf is a medical geneticist who the director of the Heflin Center for Human Genetics and chairman of the Department of Genetics at the University of Alabama at Birmingham. He was associate professor of neurology at Harvard Medical School and directed postdoctoral training in medical and laboratory genetics at hospitals affiliated with Harvard. Dr. Korf's principle area of research is neurofibromatosis type 1. Bruce Korf: My name is Bruce Korf, I am a medical geneticist and my role at University of Alabama at Birmingham is associate Dean for genomic medicine and chief genomics officer. I do a fair amount of work in rare disease, both diagnosis and management and have a longstanding special interest in neurofibromatosis, a genetic disorder that affects the body in many ways, but especially causes tumors of peripheral nerves. Nate: I want to ask if... for the casual searcher who's going online or maybe he's heard that a family member or a loved one is possibly being diagnosed with this disease or has recently received a diagnosis, what would you say to that person? As far as what they should know and what sometimes some of the misconceptions might be about NF? Bruce Korf: Well, NF is a condition that is complicated because it affects many systems of the body and is notoriously unpredictable. So it can range from a pretty mild condition that doesn't have any major medical complications to something that can be very serious, disfiguring and in a few cases potentially even life-threatening. And from one person to another, even in the same family, it's really difficult to predict how it's going to behave. Bruce Korf: And on one hand, that means that there will be a great appetite for accurate information that families will have or infected individuals will have and they'll be very eager to learn what they can. On the other hand, it means that if you just go online and do a search, at best you'll get pretty mixed messages about what to expect and at worst, sort of distorted view of the condition. And part of that's because some of the most dramatic and severe problems are the things that motivate people to put information on the internet in the first place. Bruce Korf: So you tend to get a somewhat skewed view of the way the condition might present, skewed towards the more severe, more serious outcomes. And hence a person, especially first learning about the condition can be pretty shocked to see some of the stuff that's out there and not realize that it represents just one end of the extreme. Nate: That makes a lot of sense. What are sometimes the conversations that you have the first time someone comes in, is it bringing them down from some of that information that may have been online or is it kind of a mixed bag of where they come in as far as their knowledge when they're just starting to speak to you after diagnosis? Bruce Korf: Yeah, a lot depends on what led to the diagnosis in the first place. So a very common reason to see people for the first time is a child that has just cafe au lait spots, brown spots on the skin, which together with some other features that by themselves are fairly subtle and not medically concerning could add up to a diagnosis. And so these are parents of children who are basically healthy but have enough signs of the condition that you can establish the diagnosis. Bruce Korf: So that's one side of the coin, the other side are people that first come to our attention because some significant complication has occurred already and therefore is already declared itself in that particular situation as a fairly significant medical issue. So how you explain things obviously depends on where that particular individual or family is coming into the system and what they're already dealing with versus things that may or may not ever occur. Bruce Korf: What I do find is, is helpful though, and this probably applies across the board, is there's certain things that happen in neurofibromatosis pretty early in life if they're ever going to happen. An example would be some of the bone disorders that can occur, like curvature of the shinbone for example. These are things that get going early on and if they happen, they can be fairly significant. But if they don't happen, you can be reassuring that that's a complication that is just not going to happen after a certain point. And a lot of families don't realize that. So they come in and if a person in the family, a child oftentimes, is already five or six years old and has normal bone structure they have this fear that suddenly this is going to change. And you can actually reassure them that if it was going to happen, it would have happened by now and since it hasn't, it won't. And I find families are often surprised to hear that and very definitely reassured. Bruce Korf: I guess the other thing that happens a lot is with any rare disorder, most physicians or health providers have limited experience with the condition and sometimes either give misleading information or just don't know enough about it to give complete and accurate information and so they tend to be pretty vague. And so many of the patients we see have been frustrated just by not talking to somebody who has real experience with the condition and when they do it is eye opening for them and is a really helpful thing to be able to place the condition into proper perspective. Nate: I wonder what your advice might be for patients who just don't know if what they're being told by their physician is accurate or the best information. I certainly can understand that there are those out there who just don't have enough experience with this to be able to give accurate or up-to-date information. What's a good barometer or way to check against that, is to speak to multiple physicians, is it to reach out to the patient organizations? How do you think someone could approach that? Bruce Korf: Yeah, well, I guess when you're dealing with a rare disorder, and this probably applies to almost any rare disorder, it really helps to talk to somebody who does have experience in managing it. And so one of the kind of fundamental questions is, are you talking to somebody who has sort of book knowledge of it or is really immersed in taking care of it? And how do you figure that out? Bruce Korf: Well, in the case of neurofibromatosis, for example, the Children's Tumor Foundation, a patient advocacy group dedicated to NF, maintains a list of clinics that identify themselves as having expertise in NF and I think is a pretty reliable source of information because clinics on that list are identified for having... seeing a fair number of patients and often times for having published papers in the area so it's a reasonable indication that this is a group that has enough experience to be authoritative. Bruce Korf: I realize it's not always so easy to find such a clinic in your immediate area. So there are plenty of places where there isn't a nearby clinic. That's true in the US to some extent and it's definitely true around the world. So it's not always so possible for a person to get to be seen in a place. But if they can be by far, that's the most reassuring way to know that you're talking to somebody that has enough experience to be authoritative. I would also say patient advocacy groups dedicated to the condition, in this case, for example, the Children's Tumor Foundation have, I think really good quality, reliable information. So you can to some extent use it as a barometer of what you're being told and how well does it accord with the kinds of things that are put out by that particular organization. Nate: Switching gears a little bit. Something that we haven't talked about yet with this disease is clinical trials and I know that's something that you have experience with. How does someone go about finding a clinical trial related to NF? How do they evaluate them? How might they choose one? What is your best advice for that? Bruce Korf: Well, the best advice is to use the clinicaltrials.gov website. It's, as the name implies, a government run clinical trials database and pretty much all clinical trials in this country at least would need to register themselves with clinicaltrials.gov. And it contains on it, first of all, it's searchable by condition and by even complication like plexiform neurofibroma or bone dysplasia or things like that would be searchable. So you can find up to date information about active clinical trials in that context. And it will also have information about eligibility criteria for the trial, where it's being conducted, what the trial actually involves. Bruce Korf: It provides a pretty good amount of basic information to help identify and explain the trials. Now ultimately, if you're interested in participating, there would be a contact address or an email that you would then need to contact the investigators to figure out where things actually stand and whether it might be a feasible option for a given person to participate in the trial. Nate: What about you personally? I mean, is that usually the advice that you give patients that come in? Or are you typically staying up to date on current trials? Should they expect their physician to sometimes be up to on those things or just go to clinicaltrials.gov, see what you see and then we can come back and talk about it. Bruce Korf: Well, again, if it's a clinician who's really an expert in the field then, yeah, you would expect that they would have a pretty good idea of what's out there. I feel like if I'm seeing an NF patient, first of all, I think I do have a pretty good finger on the pulse of what the major trials are. And frankly, if I'm dealing with a manifestation of NF that's unusual where I might not have as much experience, I actually would go to the clinicaltrials.gov site before the patient would to make sure I'm not missing something because it's a moving target and not all the trials are widely publicized. So I don't think anybody has a monopoly on complete knowledge of what's out there. But sure, if you're focused on the field it is something you're probably aware of, but also something you probably would double check. Nate: I guess finally, we've spoken with some genetic counselors about different disorders and we work with some here at our company and people I feel like are often very curious about who their team might be when they receive a diagnosis of a rare disorder and something like NF with various symptoms and manifestations. It could be a number of things, I guess, but specific to genetic counselors, I guess to ask you, what role do they sometimes play in kind of the team aspect of those within NF diagnosis in your clinic or just in general and what role could they perhaps play? How should people think about GCs? Bruce Korf: Well, genetic counselors, if you kind of look at their core expertise and role, it would usually be to help individuals understand how genetics contributes to a disorder and offer information about risks and various options that exist to deal with those risks. That's the sort of core skill of a genetic counselor. So taking a family history, discussing genetic test options, what the recurrence risks are, what are the options to manage those. But they also tend to play a role when a diagnosis is made such as NF in helping people understand the natural history of the disorder and what to expect. Bruce Korf: And in some cases they may play roles of helping to coordinate care and provide information on what kind of surveillance is recommended and where and how can that be achieved in terms of, do you need referrals to other clinicians. Now, in that case, they're part of a team, that may be something that the physician that's involved will help to guide, sometimes the counselors serve as sort of clinic coordinators. That's not always by a counselor, in some cases, it might be done by a nurse or a nurse practitioner so there's different models depending on the specific staffing. So the kind of core of genetic counseling is really dealing with genetics per se, but they tend sometimes to play larger roles of clinical coordination when it comes to genetic disorders. Nate: Well, I guess finally I did want to ask is there anything in and around NF that is new exciting developments that have happened in the last year or two, whether that's on the treatment side, new information from testing that may not be widely known yet or is something that might be relevant that you'd want to include here? Bruce Korf: Well, I think the area that's most exciting is there's been a fair amount of progress in development of therapeutics. And we do now have a family of drugs collectively called MEK inhibitors that have been shown in various clinical trials to have some significant effectiveness in helping to shrink, especially plexiform neurofibroma, that seems to be the major target. So there are drugs, some of them are available either for off-label use or under some circumstances for compassionate use. Bruce Korf: We're still waiting on FDA approval and we're hopeful that there will be an FDA approved drug at some point in the near future. We're not quite there yet, but that seems to be the direction things are moving in. And so it really has changed our way of thinking about management of NF because in the past some of these tumors were deemed to be inoperable and there was pretty little you could do other than trying to remove some of the excess bulk if there were major symptoms, but that was a pretty unsatisfying approach and sometimes just not possible. Bruce Korf: So now there actually is the hope that there will be some nonsurgical treatments. And although I wouldn't describe it as routine just yet, it's pretty clear that's where things are going. And meanwhile, we have other clinical trials that are either underway or being contemplated that we believe will continue to make a dent in the way these patients are treated in a really positive way. So I'm hopeful that over the coming years NF will turn into much more of a kind of a chronic treatable condition and less of a, well, we're just going to wait and watch, but there's not much we can do. Nate: Thanks to Dr. Korf. Next we spoke with Emily Sites. Emily is a licensed genetic counselor with a specialty focus in neurofibromatosis and she is the coordinator of the neurofibromatosis clinic at Nationwide Children's Hospital in Columbus, Ohio. Emily: My name is Emily Sites, I'm a genetic counselor. I work in pediatrics at Nationwide Children's Hospital in Columbus, Ohio. Nate: Great to have you Emily. So tell me what comes to mind first and foremost for you, when you kind of hear the letters NF? Where are those initial conversations? What are the context of those that you're having with patients that come in the door? Emily: Yeah, so a lot of times patients don't really know what NF is when they come to see us. They've been referred by their doctor and maybe they've been told a little bit about why they're coming and maybe they haven't. Maybe they just know, I have these birthmarks, these café-au-lait spots, but I don't know too much else. And some people they say, "Yeah, my doctor said neurofibromatosis, but I don't know what that means." Or some people have pretty extensively researched it before they even come to the clinic. So we try to find out first where are they coming from, what's their level of understanding so I know how much I should be explaining to them upfront. Nate: Is that something that you guys do in an introductory phone call, but prior to a office visit or a clinic visit? Emily: Typically, it happens when the patient arrives. I introduced myself and I kind of say, "Do you know why you're here today?" And try to assess out what their level of understanding is. Nate: Okay, what role do you play as a genetic counselor kind of in the team and the process and the lifespan of being diagnosed with this disease? What should someone who is maybe researching this for a loved one or a family member or has maybe received a diagnosis themselves, how should they think about genetic counselors in the role that you play? Emily: Yeah, so genetic counselors are really there to kind of help you along the way. We're there to make sure that you are understanding everything that you're getting all your questions answered and that you are being put in touch with whatever resources you need to manage your health or the health of your loved one, of course. Sometimes doctors don't always have a ton of time to spend in exam rooms talking to patients but counselors do have that luxury a little bit more that we can spend more time chatting with you, getting to know you and hopefully answering your questions as much as possible. Nate: Is this an ongoing relationship where you're talking to patients over the course of weeks, months, years? Emily: Absolutely, that's one of the things that actually really drew me to the field of neurofibromatosis in the first place is that I do get to develop these longterm relationships with a lot of my patients, first, when they come in initially for evaluation and then when we're ultimately sharing that diagnosis with them and kind of guiding them through what the future treatment and management will look like. And then in our clinic we see patients back ideally once a year so I get to watch these kids go up and I get to watch these families grow and mature and change over time over many years, it's very rewarding. Nate: What's different and unique about where you are now at Nationwide as far as the neurofibromatosis clinic and maybe how you guys treat and interacts with patients if it is in fact unique, which I'm sure it is. Emily: One of the things that I love about our clinic is that the one of the geneticists that runs the clinic, Dr. Madigan, he's actually also bordered in adult medicine. And so he can see adults with NF as well as children, which is really great because there aren't a lot of centers, there aren't as many centers that see adults as there are that see children. And so we can see the whole family because many times this is inherited. So about 50% of the time when we see a child with NF, their parent also has NF and sometimes brothers, and sisters, and aunts and uncles. So we feel very fortunate that we're able to care for the whole family in cases like that. Nate: I think that is really unique. I know that in some of the other conversations we've had, there's kind of two things that can be limiting or a challenge and that's like good information, access to it and also just geographic restrictions, kind of based on where you're at. If you receive a diagnosis of this and you live in rural Montana or even in a larger city that maybe just doesn't have a clinic like yours, what's your best advice for people in those situations. Emily: So there's a tool on the Children's Tumor Foundation website, which is just ctf.org and you can actually find a doctor or find your nearest NF clinic with that tool, so that would be the first place I would look. But otherwise it's hard to know who's the specialist that I should go see if a genetic specialist isn't nearby, but there are lots of other specialists that care for people with NF, it could be a neurologist, it could be an ophthalmologist. So there are other providers that are more widely available than geneticists so I would use that CTF resource first and then ultimately I suppose either talk to your primary care doctor about who they could recommend locally or reach out to a genetic counselor through nsgc.org and they can maybe point you in the right direction. Nate: What about some of the patient organizations and support groups in and around NF? Which ones do you recommend or have you interacted with? Emily: Yeah, so I mean I've really not come across an organization that I wouldn't recommend. I think they're all fantastic and they all obviously have a goal of supporting patients and families. CTF, the Children's Tumor Foundation is one that I've worked with quite a bit. I think they're fantastic. They raise a lot of money and sponsor a lot of research and a lot of cutting edge developments are coming out of that. And they do a conference every year for families, it moves around the country every year. But I think that organization is doing a lot of great things. When I was in Chicago, I worked with, a little bit more with NF Midwest and they are I think a subgroup of a larger organization called NF Inc., I-N-C, and that is also a great organization. Nate: I want to ask about when someone comes in for their first visit and maybe they have done some of the research online. When you hear that does your guard go up? Are you concerned about what they've found online? Which resources do you trust for good information? Emily: Yeah, I wouldn't say my guard goes up but I definitely... I ask a follow-up question, which is, did you read anything that has you really worried? Because sometimes they come in with that really weighing on their mind and it's hard for them to really focus and pay attention to a lot of the stuff that we're saying if they've got this big fear looming over them. So I tried to find out, what did you read that you're concerned about? And if I can put those fears to the side right away, we can do that and then we can move on. So that's typically my approach if they've done a lot of reading. Emily: In terms of resources that I recommend and that I trust, we have some great literature that we can provide to families in the form of booklets and pamphlets that primarily the ones that do come from the Children's Tumor Foundation, again, they have a great patient resource section on their website and that families can actually just print those things out for free. But we have them bound and in color and on glossy paper and stuff in our clinic that we can give to families, whether it's a new diagnosis or it's a mosaic diagnosis or it's NF1 or if it's NF2, we have different literature for all of that, for if you're a teenager, if you're Spanish speaking, so those are all great resources that we tend to share with families the most. Nate: Yeah, that's fantastic that you have that. I know that spanning all of rare diseases, that's not always the case that someone can easily find something like that, let alone find it in their area so that sounds highly valuable. Emily: I think the university of Washington in St. Louis also has some great resources on their website for [inaudible 00:40:48]. Nate: I know in some of our other conversations we've kind of talked about new treatment options that have come around for NF for extending quality of life, changing quality of life. We've talked a little bit about clinical trials as well. I mean, in your clinic and your experience with neurofibromatosis, what do you say as far as new treatment options or treatment options, how things evolved as far as the options for those who are diagnosed with this disease and the kind of the prognosis for what they can expect going forward. Emily: Yeah, it's an exciting area that there's a lot of research being done on primarily how do we stop tumors from growing or how do we shrink tumors that are preexisting to reduce the morbidity in the mortality of those. And that would be the most active area of research I think right now that patients are really interested in of course because that can be a big quality of life issue for them. So yes, there are definitely active areas of research into that and yes, there are some exciting clinical trials that are happening specifically with a lot of MEK inhibitors right now. So I think there's still a long way to go, but I think we can say to someone who is coming to us with a young child in their lifetime I think we're going to have much better treatments available for these kinds of things. Nate: You primarily do deal with children where you're at, correct? Although you mentioned that- Emily: Primarily, yeah, because we are children's hospitals so that's the majority of referrals that we get. But then again, 50% of them come in with an affected parents so sometimes we do end up seeing the parents as well. Nate: Is there a difference in kind of the diagnosis part? Well, not just the diagnosis, but more of the prognosis and suggested treatment options and things like that for someone who's aged two or five versus 25 or 50? Emily: Yeah, definitely. For kids, they don't tend to have a ton of symptoms related to their NF. Usually the first few years are pretty quiet. I mean, there's definitely exceptions to that. Kids are certainly the highest risk group for things like optic pathway gliomas so we have to watch them closely for that. But when you're talking about the more burdensome tumor types, the larger plexiform and the malignant peripheral nerve sheath tumors, the MPNSTs, those we tend to see more in adults. Emily: So when you're seeing an adult, you have to talk more about tumors and when you're seeing a child, you're usually talking more about school issues, attention deficit disorders and just screening for optic pathway type of tumors. There's a newer recommendation now for women starting at age 30, that they need to start their mammograms. So definitely a lot more conversations about tumors and things when you're talking to an adult. Nate: Very good. I mean, anything in closing that you feel like you'd like to say to someone who might be out there hearing this that's researching this disease, whether it's misconceptions or just good advice that they might need to hear. Emily: To patients, I always say when they're being newly diagnosed, it seems like it's something that's very scary right now, but the majority of people who have neurofibromatosis type 1, they really lead very normal and healthy lives. They get married and they graduate from school and they have families and they have jobs. Most people are not going to have really severe complications from this, although it can always be scary to read about those things on the front end. Emily: To other providers and people who are just generally researching neurofibromatosis, I would say it's extremely common. It's one of the most common disorders, genetic disorders that there is one in 3000 people. So there's a lot of patients out there that are living with this and I think we still have a long way to go in terms of developing better treatments for this. So I would encourage anybody who's interested to pursue that line of research and that line of work because I think that there's a lot of opportunity there for us to develop new therapies and improve the lives of people with NF. Nate: Thanks so much Emily. Finally we spoke with Annette Bakker. She's the president of the Children's Tumor Foundation and also the chief scientific officer. In 2017, she was awarded with a rare champion of Hope Award. Here's Annette. Annette: So I'm Ann, I'm a Ph.D. biochemist. I started my Ph.D. quite a few years ago and I did both about... For 10 years I was in the academic part of the world if you want. I was at both medical school and I'm [inaudible 00:45:40] and in Antwerp. And then I kind of got that what now feeling. You do all these basic discoveries and I felt that there was that misconnection between basic discovery and a true clinical benefits. And that was... that has been, in fact, the drivers throughout like what can you... how can you do a discovery and actually make sure that that discovery makes... results in better treatments for patients. Annette: So I joined the oncology group in J&J, I was for about eight years with J&J in the oncology group, mainly in the translational science part. So really translating discovery into clinical benefits. Then I was recruited by headhunter to start, design and open neuro-oncology department in the biotech in Italy where I then headed the neuro oncology department for, and I was part of the executive management of that biotech. And then in fact in... and I was in the glioblastoma, so the brain tumor field at that time. Annette: And then in fact, the thing that really made me start looking for something else was that that disconnect between academic research and actual clinical benefits as... that gap to me was really too wide. And very specifically, there was a great paper that was published in 2006, new mechanisms, very large cancer [inaudible 00:47:08] paper that was published with new mechanisms for glioblastoma and I was like, "Okay, this is not a time where we'll be able to really develop better treatments." Annette: But the first thing that you need was also access to better models, better animal models, better cell models, and in fact it didn't happen. Everybody kind of stayed in their comfort zone and the translation didn't happen. And 10 years later people are still treated with primasol or might have radiotherapy. Annette: So kind of my, let's say my frustration drove me to start looking for opportunities. And that is where I literally found in a news magazine, I found the position at the foundation and I thought that is it, that is the Switzerland organization in general, the non-for-profits. I think are the sweeter one, Switzerland they can really push everybody a little bit out of their comfort zone because they really have only one client at the end of the day, which is the patients. So I joined the foundation in 2011 as the chief scientific officer and since 2014 I'm the president of the foundation. Nate: Tell me some of the things that have happened since you've joined. I mentioned, just a cursory look at the website it's very impressive just the amount of resources that are there, the things that are explained, the registry, and it's something that you can't find on all a rare disorders. Tell me a little bit about what's been accomplished and what you feel like is unique about CTF. Annette: Over the last five years, I think the most... the biggest impact that we've had on the NF community is that we've tripled the number of clinical trials in five years, which I think was really... that really speaks to what we did all the right things. The second thing we did is, and not only have we created that increased number of clinical trials, but we've really built a diversified portfolio. We're not going to focus... A lot of the rare diseases are really interfocused on gene therapy now. Annette: We really have to taken almost like an investment portfolio to say, "Okay there are drugs today that we can use for NF, there are biologics today that we can use for NF and then there is gene therapy which may... which of course in the holy grail if it works, but let's not put all our eggs in one basket." So we've really built a diversified R&D portfolio which I think was the first for NF. The third thing that we've done is we've really built a very vibrant community because we're really convinced that every single stakeholder, whether it's the patient, researcher, the clinician, the FDA, the pharma company, the funders, all of them are really an integral part of the success of what we hadn't been able to do for the last couple of years. Annette: So we've really built a community and we've also on top of this research and clinical ambition community, we've also built a data community. So we ask the researchers to share their data in a data hub as we're funding computational biologists that are really integrating that data and they can show that the data is usable again by the community. And then those lead to hackathons to all kind of cool stuff that we could do because of our researchers being willing to share their data. And then I think the last thing is, of course, the hottest of all is the selumetinib, is the first drug for NF that is so far it's actually at this point in time at the FDA with a request for approval. So we are all hoping and dreaming and relatively optimistic that we may have one first drug approved for NF which, of course, then it's leading to an increased interest on pharmaceutical companies in NF. Nate: How have you successfully been able to pull together that community? There's so many different stakeholders and you look at some other disorders and there's random Facebook groups and sometimes kind of, not half-hearted efforts, but a kind of stop and start efforts I think to bring people together. What are one or two of the things that have worked for you in bringing together both the patient's side and then also connecting them to the researchers and the pharma companies? Annette: I think what is really important is to communicate well what it is that you're trying to do. And I think we've had a hard time communicating that because it was difficult. But now I think we're pretty clear, we just had a Faster Cures webinar in which I made out what it is that we were doing. And in fact, everything started with the observation that whether it's the clinics, whether it's the academic communities, whether it's a commercial enterprise or whether it's the regulators, it started with an observation that all of them were operating relatively siloed and that there was really a need. If we would want to make sure the discoveries actually make it to better treatments for patients, we really need to pull in all the stakeholders including the patients. And so while we started with a dream saying, okay, can we meet... can we connect all these communities to each other? And so all the investments we have made are in fact with that philosophy in mind. Annette: So we will still put a pretty impressive bucket of money towards new discoveries because only new discoveries will lead to better treatments. But then as soon as new discoveries are made, we have built an R&D, we call it the R&D enabling platform. So we've really built a platform of assets that pharmaceutical companies need. Whether it is a patient registry, whether it's a clinic network, whether it's a bio bank, whether it's a data portal, whether it's a key opinion leader network, whether it's for clinical models, whether it's the task for approval. Those are all things that pharmaceutical companies really need in order to set up a new disease area such as NF. So we have built that platform. We've built that... I always say that the table is set just come for dinner. Annette: That is in fact, we wanted to make it so easy for companies to enter into the NF space. And then on top of that we would do with our research team, we will do the research and say, "Hey Mr or Mrs big pharma, or small bio team, did you know that you have a drug in your pipeline that could potentially benefit NF patients?" So we have been very proactive to pull the patients into this exercise. Annette: As you hear, I'm not American, I'm not an English native speaker. I had to learn many different languages because I was part of my life in France, part of my life in Italy, part of my life in Belgium, part of my life in the US and I really think that research is a language and that sometimes patients are scared and think that they don't understand research just simply because they don't understand the linguistics of research. Annette: So what we have done is we have put in place a patient engagement, a patient training program, like a language and another collaboration with European Patients' Forum is to say, okay, what is it that our patients need to know in order to understand research and development, in order to understand what is a clinical trial, in order to understand what does it mean patient reported outcome, what does it mean to participate in a clinical trial? What is it that you can do? What is it that you cannot do? What is... how do you discover new drugs? Et cetera, et cetera. So our patients have really been trained to be advocates for themselves and their children and they are now acting as the reviewers for the grant. They're acting as a... they're acting on patient adboards for companies. They're going to the FDA to explain to the regulators what it means to live with NF. Annette: So they're really part of the community. And I think that has created so much energy that you create a kind of magnet, if you want, of patients that say, "My kid is sick, I am sick, I want to do something." Well, at CTF people can really do something. And I think that is what has attracted... what has made our foundation attractive for patients is that they really feel that they can act. And we have now a classroom that care and we have a youth program and we have a lot of fundraising programs. So it's kind of creating that community of hope for patients, which is really something that we are very, very focused on. Because as you may hear, I always say I'm pathologically optimistic. So that creates an optimistic and my whole team is pathologically optimistic so that creates an optimistic, hopeful community. And people, especially when it's difficult, people are looking for hope. So I think that is what we want to offer to patients, not just empty hope but hope you can actually do something. Nate: You know when I asked about some of the top accomplishments, the first thing you mentioned was increasing the number of clinical trials that are happening. It sounds like creating that patient engagement platform is a key component to that because when you know you have the patients there engaged, ready to participate, so many clinical trials, at least to my knowledge suffer from patient recruitment issues. And if you've got a built in network of people advocating for themselves that makes it happen. And it's right and poking around here, I guess from the patient perspective they come to CTF website, they've got a bunch of different options from... I love the recently diagnosed linked or newly diagnosed, excuse me, where you can kind of just get to know things, but there's so many different tools about finding doctors. I guess the main step for them after kind of getting to know poking around the organization is to join the registry, sign up and kind of start participating in the platform. Annette: Yes, and especially for a rare disease but there's that other aspects of raising awareness. So some people don't feel comfortable to fundraise, but they are very comfortable in raising awareness for NF, which is super important as well for a disease, especially for a rare disease. So we have now in May a Shine a Light on NF, which means that buildings are lit up in blue and green to really raise the amount of... let's say to raise the awareness of NF and also really make sure that more and more people know where the NF is. Because still every day I meet people that I have no idea what the NF is. But then when you start talking to them, a lot of them have actually very close friends or family with NF. So it's a very... I mean it's two and a half million patients with NF so everybody knows people with NF and although nobody's heard of it I will say it's the best kept secret, right? Nate: I see also here that you guys have a calendar of events. I know it's an odd time for events, for in person events right now when we're recording this, but tell me about some of the events you do have and if there are any that are like the main event that folks might keep an eye out for or something like that. Annette: Yeah, so the whole idea that we have when it comes to events is that it's very volunteer-driven. A lot of our volunteers say like, "Hey, we would like to do walks or we would like to do an endurance event, or I really feel strong that I want to do a tea party for my friends and family." Or as you can see and be, let's say in the fundraising environment there is a lot of opportunities to get engaged with the foundation. And there is, of course, the direct donation page obviously that people can always make direct donations to support our work. But there is also volunteer opportunities, volunteering in the volunteer leadership council. So there's a lot of volunteering events like kind of helping out in walks around in endurance events, volunteering to help out the community. I think that is also a very important thing, volunteer to advocate for NF. Annette: We have a very large advocacy program also in collaboration with some other NF founders, which means going on the... There is a program which I didn't tell you about, which is called the Congressionally Directed Medical Research Program, which is an annual allocation of a budget anywhere from 10-15-20 million by Congress to NF research. And our patients as well as our own staff members will go on the hill to advocate for NF and to advocate for CDMRP funding. And then of course, as I said before, there was a really important component of volunteering to raise awareness in a million different ways. The Shine a Light is one of them, but if people have other ideas and we really like to put it in the hands of our community to come up with ideas of how can we fundraise, how can we raise awareness? That's really important. Annette: The last aspect is there is also an educational component that we offer not only by on the brochures that you've just mentioned but also on NF Forum, which is an annual event where patients come together to be educated about NF and where it's also really a community building opportunities for people to come together. And then, of course, never to forget in summer we have the NF Camp, which is really for younger kids, with NF. I'm saying kids and I'm hesitating because it's all the way from 12 to 20 that are having the opportunity to come to our NF camp in Utah. And then we have a partnership with an organization called Cupid's Undie Run who was kind of a fun event in February where they run in their underwear for NF awareness and for fundraising. And that's our partner organization. Nate: Perfect, I think it's a good rundown and I know that everyone can check all that stuff out at ctf.org. I guess finally I wanted to ask is, you're speaking to someone who's so deep and kind of in this world, in this community, in and around NF, is there anything that's exciting right now that's in development or coming down the pipe that gets you excited that others who are maybe just discovering NF or have recently been diagnosed or someone that just maybe searching around this disease might not know? Is there anything else that you might want to clue them in on or explain about what's going on right now? Annette: I'm very excited right now. I always say it's a very weird time because on the one hand we have Covid that is kind of putting us down all of us. But on the other hand, in the NF field, it is beyond exciting. So we have selumetinib that we're waiting, obviously, to hopefully have it approved. We have a number of clinical trials in NF that are coming down the pipeline at a very fast pace and there's a lot of energy from the pharmaceutical company sites. For NF2 we have... so the selumetinib is for NF1. For NF2 we are on the cusp of trying... of starting a big platform trial and a platform trial is really a trial that will allow to test multiple drugs for multiple mutations in parallel. Annette: So the first drug is a collaboration with large pharmaceutical companies so that trial will start very soon. For schwannomatosis we have a large consortium which is called [inaudible 01:02:30] which is really a global consortium of experts. They are discovering new mechanisms for Schwannomatosis. So there is... and there is a general enthusiasm in the pharmaceutical company and bio if you want for NF. So we have calls almost on a weekly basis with companies that are interested in NF. Annette: So I think we are seeing a lot of very high energy in the NF community. There's also investments both from us and from some other organizations in NF1 and NF2 gene therapy. So I mean we're shooting around and it's really an exciting time for NF. So we're beyond happy with what's happening in the NF space and we have an... as I said, we have an extremely vibrant community. Nobody is sitting down waiting for it to happen everybody is participating so it's really cool. Nate: Thank you Annette. Thanks to all of our experts in this episode. We've been told that being diagnosed with a rare genetic disorder feels a bit like you've been thrown into the middle of the ocean without a life raft. We all find ourselves with a small bit of information that only leaves us wondering, "Okay, what now? So what now?" We know that hearing from these experts is only the beginning for you. That's why we've taken this information and included in the downloadable guide that you can access at raredisease.com/nf. Go there, download a recap of this episode and get key points as well as several links and resources for you to further explore. Nate: Finally, if you do need to speak with someone directly about NF or your personal situation we're here to help. Visit raredisease.com to get in touch, we're standing by. This is rare disease connection, a production of Aspect Health and raredisease.com.

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