WHAT IS NF?

12/7/2016

NEUROFIBROMATOSIS (NF) is a genetic defect that affects about 1 in 3000 children; and causes tumors to grow along nerves. NF stems from genetic defect in certain chromosomes. Depending on severity, NF impacts the child first and foremost, and most probably the impact extends to the immediate and extended family too. The impact is both physical and emotional; the more severe the NF the more severe the impacts.

Victor Chukwueke was awarded the Strength and Honor Award by the CTF in 2013. Victor is an amazing man who has met and conquered more challenges than most anyone his age. Victor is currently in medical school at the University of Toledo. This links to the CTF video where Victor gives a very moving description of his life and challenges. In a few minutes he teaches us about the many challenges of NF and how he conquered them. He established Victor’s Hope Foundation to benefit the less fortunate throughout the World. Victor sets the example that applies to any one of us regarding what it takes to meet life’s difficult challenges (not only NF) and to conquer them.

NF1

NF1 is the most major category of genetic defects that falls under the NF umbrella. NF1 by far represents the vast majority of NF cases. In the paragraphs below Vincent Riccardi, MD writes a most current description and definition of NF1.

He concludes his write up with the following: ” In sum, we are entering into a new era and there is strong reason to expect – soon – an expansion of current treatments, as well as realistic new treatments to avoid major NF1 problems.”

WHAT IS NF1?, Vincent M. Riccardi, MD

The three alpha-numeric characters, N, F and 1, are currently used to designate two logically related entities: NF1 – the human genetic disorder and NF1 – the gene (gene locus), which when mutated or deleted, causes the disorder. (In print, the three characters are italicized when they symbolize the gene.)

In order to understand NF1, the disorder, it helps tremendously to consider several key things about the NF1 gene. In humans it is located on the long arm of chromosome 17 and each person has two copies (alleles), one on each of the person’s two chromosome 17s. The NF1 gene, in one form or another, is present and important in all forms of earthly life that have a cell nucleus – from yeast and amoebae all the way to primates, including humans. In all species studied, NF1 seems to be critically important to survival. It is a very large gene, like a long freight train with many box cars, in contrast to a pair of trolley cars. Consistently it is involved in assessing the environment, regulating nutrition and biochemistry and survival. In vertebrates, it is critically important for the formation and function of blood vessels, the skeleton and the nervous system, including the brain, spinal cord and peripheral nerves. In humans it is especially important for “fine-tuning” our behaviors, adding a unique finesse to our sensibilities and performances. It does this by being a control element – a switch or rheostat – at multiple biochemical, physiological and anatomic levels. If one of the NF1 alleles is damaged (mutated or deleted) an organism is substantially compromised. For humans, the sum of those compromises is referred to as the human genetic disorder, NF1.

Ordinarily, the origin of human syndrome, NF1, is an NF1 gene mutation or deletion in a germ cell, with mutations more likely in sperm and whole gene deletions more likely in eggs. The resulting zygote (conceptus) thus has only one normally functioning NF1 gene and the newborn child we say is affected with the disorder, NF1. How this genetic defect accounts for each and all of the NF1 syndrome elements is now the subject of intensive studies worldwide.

Let us start at the level of the organism, the person. Most often, at birth or days later, the NF1 syndrome is apparent. The NF1-affected child may appear totally normal at birth, but this is no reason to expect that the disorder will always be minimal or mild. This is one of the disorder’s most perplexing elements, from both the perspectives of the individual/family and researchers. This point is emphasized early on because, when we talk about “what is NF1?” we must speak in generalities and “averages” for large populations of affected persons. This is key: listing and categorizing all of the elements of NF1 does not depict the situation for a particular person. On the other hand, awareness of the entire range of problems alerts the person/family and clinician to what is at stake. As well, to some degree, the onset of certain problems are age-related. Puberty in particular is a time when NF1 neurofibromas become more intrusive, either in terms of newly appearing or worsening. These considerations respected, let us consider the disorder more specifically, understanding that this is an overview, not an in-depth encyclopedic itemization.

So, what is NF1? The NF1 gene alteration is ordinarily present in all of the body’s cells, but most of the disorder’s elements reflect biochemical dysfunctions in cells from the embryologic Neural Crest, including pigment cells in the skin (melanocytes), support cells in the brain, spinal cord and nerves (astrocytes, Schwann cells) and selected hormone-producing cells. Other cell types are involved, including those contributing to blood vessels or to the skeleton. Fat cells – adipocytes – are involved on multiple levels. And, finally, cells involved in inflammation, namely lymphocytes, macrophages and mast cells, are major contributors. The latter, mast cells, specifically contribute to the origin and progression of neurofibromas.

These cellular disruptions lead to mass lesions, both benign and malignant, structural blood vessel and skeletal abnormalities, and various types of functional abnormalities, including intellectual disturbances. The disorder gets its name – Neurofibromatosis 1 – from the typically large number of neurofibromas: these mass lesions involve the skin and various lengths of individual and interconnected nerves (plexuses), some very close to the brain or spinal cord, some at the nerve endings and some in between. The neurofibromas restricted to the skin (cutaneous neurofibromas) may cause local dysfunction and often are disfiguring, but the do not become malignant. The other types of neurofibromas, i.e., subcutaneous and plexiform, have a minimum 15% risk of malignant transformation.

The visual apparatus of the brain – the optic pathways – accounts for tumors in 15% of NF1 persons. Most often they initiate in childhood as a benign optic pathway glioma (OPG). Either by transformation of an OPG, or arising de novo, a malignant form, glioblastoma multiforme (GBM) may develop. Occasionally, a glioma or GBM may develop in other parts of the brain, but, distinctively, not in the spinal cord. In addition, several other types of cancer, including breast cancer and a specific type of childhood leukemia, are also more likely.

Serious skeletal problems include deformities of the shin bones (tibial pseudarthrosis), bones around the eye (sphenoid wing dysplasia) and the vertebrae (vertebral dysplasia and the associated dystrophic scoliosis). Interestingly, height tends to be lower than average for those with mutations within the NF1 gene, while higher than average for those with NF1 whole gene deletions. Cardiovascular problems range from large structural changes (dysplasia) through small structural changes (angiomas) to aggravation of underlying hypertension and/or atherosclerotic abnormalities. The gastrointestinal tract may be involved in a variety of ways, including nerve overgrowth in the large intestine (hyperganglionosis), a specific type of stomach lesions (gastrointestinal stromal tumor or GIST), and intestine-localized neurofibromas.

The intellectual and performance problems occur in at lest 60% of NF1 persons, ranging from mild developmental delay through to frank mental retardation. A consistent association is decreased attentiveness, often to the point of warranting the designation of “attention deficit disorder.” It is noteworthy that persons with the NF1 whole gene deletion have an earlier onset and more sever outcome in these regards. There is a small excess of seizures among persons with NF1.

It is also important to emphasize that NF1 persons may have some traits or other frank disorders coincidental to the NF1 syndrome. This is important to recognize so that coincidental problems are not automatically presumed to be part of the NF1 syndrome. Such confusion occurs all too often, especially among older adults with NF1.

Treatment of NF1-related problems has relied on surgery and the nonspecific use of medications effective in other disorders, such as the use of methylphenidate for treating attention deficit and statins for treating atherosclerosis. A variety of anti-cancer drugs have been and are currently undergoing research for the potential widespread application in treating neurofibromas and NF1-associated cancers. Respecting the critical importance of the mast cell in neurofibroma initiation and progression, mast cell blockers such as ketotifen (Zaditen®) has shown some effectiveness in decreasing the itching and pain associated with NF1 neurofibromas, and in arresting cutaneous neurofibromas at very early stages, and perhaps an effect in reducing the size of some large plexiform neurofibromas. However, more work in this regard is needed, both in confirming ketotifen’s salutary effects and identifying a more potent, more specific formulation.

For the families that present with NF1, in one-third the presenting patient represents a new mutation. That is, the disorder was not inherited from a previously affected parent. However, whoever has the disorder has a minimum 50% risk of passing on the disorder. In this regard, it is essential that all affected persons receive sophisticated genetic counseling, at the least to clarify the NF1 recurrence risk and clarify any other recurrence risk considerations. Prenatal diagnosis by sampling amniotic fluid is a standard approach and, increasingly prenatal diagnosis by maternal blood sampling is becoming available. Moreover, preimplantation diagnosis has been used successfully on multiple occasions to avoid transmission to an offspring. For a woman with NF1, pregnancy can be associated with NF1-related problems, ranging from an interval increase in the size of various neurofibromas. This is most important if the mother already has major problems, for example with large plexiform neurofibromas in and around the birth canal.

Increasingly, there is intensive research aimed at a better understanding of what the NF1 gene product, Neurofibromin, does chemically. In addition, the importance of how the various cell types interact with each other (cell-cell cooperativity) within the NF1-affected tissues is finally an area of intense focus. This will help us understand when the lesion – e.g., a neurofibroma – is most vulnerable to pharmacologic intervention. In sum, we are entering into a new era and there is strong reason to expect – soon – an expansion of current treatments, as well as realistic new treatments to avoid major NF1 problems.

Vincent M. Riccardi, MD
The Neurofibromatosis Institute
La Crescenta, CA 91214
riccardi@medconsumer.com
11/23/2016

COMPREHENSIVE NF WEBSITES

For additional expert medical description of NF we refer you to three websites. Dr. Riccardi’s NFormation; Children’s Tumor Foundation (CTF); and the Washington University NF Center. They give you the spectrum of explanations from summary to very detailed.

Dr. Riccardi’s NFformation website

The CTF, formerly the National Neurofibromatosis Foundation, is located in New York City,and was established in 1978. The CTF was the world’s first NF organization.

The Washington University NeuroFibromatosis Center has a very detailed website that delves into highly technical aspects of NF. Washington University is located in St. Louis MO.

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