Introduction and History

Neurofibromatosis * is the umbrella term for three distinct genetic disorders that share a hallmark manifestation—tumor growth in the tissues that surround nerves. Most tumors are benign, although occasionally they can become malignant. Neurofibromatosis may also cause additional complications. None of these disorders is the so-called Elephant Man’s disease, a persistent misconception that sometimes alarms people who have just received a diagnosis themselves or for a child. The life of Joseph Merrick dramatized in a movie and in a play, both titled The Elephant Man, helped to focus public attention on these disorders.

It is important to note at the outset that the neurofibromatoses are classified not as diseases but as disorders. Although these two words are sometimes used interchangeably, they do have quite distinct medical connotations. A person with a disease, from whatever cause, feels ill, whereas a person with a disorder may or may not experience medical problems. People contract an illness; they are born with a disorder and it is part of their basic makeup. Many people diagnosed with neurofibromatosis experience few medical complications arising from the disorder; some are so mildly affected that they may never even receive a diagnosis.

Though they are often referred to as “rare,” the neurofibromatoses are surprisingly common. They are more prevalent than cystic fibrosis, Duchenne muscular dystrophy, Huntington’s disease, and Tay-Sachs disease combined (Table 1–1). Neurofibromatosis 1 (NF1) is by far the most common form, occurring in 10 times more people than neurofibromatosis 2 (NF2).¹ A third type of neurofibromatosis, schwannomatosis, appears to occur as often as NF2 (see Chapter 12).

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^* Italicized terms are defined in the glossary.

**Table 1–1** Prevalence of Genetic Disorders
Disorder	Estimated Birth Incidence
Neurofibromatosis 1	1 in 3,000 to 4,000
Neurofibromatosis 2	1 in 40,000
Schwannomatosis	Not yet documented but appears to be the same as NF2
Cystic fibrosis	1 in 2,000 (in white people)
	1 in 90,000 (nonwhite people)
Duchenne muscular dystrophy	1 in 3,500 males (rarely affects females)
Huntington’s disease	1 in 20,000
Tay-Sachs disease	1 in 2,500 (in Ashkenazi Jews)
	1 in 250,000 (rest of population)

Neurofibromatosis occurs without regard to sex, race, or ethnic origin. Although methods of determining incidence and prevalence vary, the National Institutes of Health (NIH) has estimated that more than 100,000 Americans have neurofibromatosis.2 About half of the cases of NF1 and NF2 are inherited or familial in nature; the other half are sporadic cases that develop because of a spontaneous change in a gene. This is not the case in schwannomatosis. These three disorders—NF1, NF2, and schwannomatosiscan present in almost any family, and any physician might face the challenge of diagnosing and treating persons with one of them.

♦ Growing Insight into Neurofibromatosis

Key events in the history of neurofibromatosis are detailed in Table 1–2. Case reports of people who apparently had neurofibromatosis began to appear in the late 18th century in various languages. Reports then continued to accumulate into the 19th and 20th centuries. Throughout that time, what are now known as NF1, NF2, and schwannomatosis were not seen as separate disorders, or even classified as syndromes. Instead, individual manifestations were documented, laying the groundwork for the genetic insights that took place starting in the late 20th century.

What is probably the first illustration of someone with NF1 dates back to the 13th century. It is credited to an Austrian monk known for his illustrations of amphibians, but may have been done by someone else.³^(p3) Another 500 years would pass before, in 1785, the first English-language description of the disorder was published.⁴ In 1793, W. G. von Tilesius wrote about a patient his professor, Christian Friedrich Ludwig, referred to as the “wart man.”⁵ The patient, Johann Gottfried Rheinhard (Fig. 1–1), had multiple fibrous tumors visible on his skin that resemble dermal neurofibromas.

**Table 1–2** Significant Milestones in Neurofibromatosis
Date	Milestone	Reference
13th century	The first known drawing is made of a man who may have had NF 1.	3 (p. 3)
1785	Mark Akenside, a British physician, publishes the first English- language description of someone with NF1 manifestations.	4
1793	A case report is published about Johann Gottfried Rheinhard, who had multiple wart-like growths covering his skin, a large head, and areas of skin discoloration. This is the most detailed early account of someone with NF1.	5
1822	In what is probably the first description of NF2, Scottish physician J. H. Wishart describes a patient with multiple intracranial meningiomas and cranial tumors, including acoustic neuromas.	7
830	Schwann identifies a myelin sheath cell that is later recognized as the most common type of cell in NF tumors.	3 (p. 5)
1882	Friedrich Daniel von Recklinghausen, a pathologist in Strassburg, publishes a landmark monograph about the disorder that would later bear his name. He coins the term neurofibroma after observing that NF tumors were composed of nerve cells and fibrous supportive tissue.	18
1880s to 1970s	Case reports are published that describe families with multiple members affected by NF1 and NF2. Physicians and researchers identify and begin to better understand the many types of cells involved and the clinical pathology of these disorders.
1978	The National Neurofibromatosis Foundation is founded by Lynn Courtemanche, R.N., Allan Rubenstein, M.D., and Joel Hirschtritt, Esq.
1979	The NF Foundation establishes the first comprehensive NF clinic. (Others will follow.)
1983	The NF Foundation launches the first national research program on neurofibromatosis in the world.
1987	The National Institutes of Health hosts a landmark consensus development conference that creates the nomenclature “NF1” and “NF2,” establishes diagnostic criteria for both disorders, and provides guidelines for treatment.	1,19–22
	The NNFF International Consortium for the Molecular Biology of NF1 and NF2 is established, in which researchers agree to share molecular and clinical data. The consortium has grown from 32 scientists in 1987 to more than 300 today, and has helped speed the progress of research into NF.
	Scientists identify genetic markers for NF1 on chromosome 17 and for NF2 on chromosome 22. This significantly narrows the search for the causative genes.
1988	The first diagnostic DNA, prenatal, and presymptomatic testing for familial cases of NF1 is developed.
1990	Two teams working independently identify the NF1 gene and describe its protein.	2,23–25
	The National Institutes of Health sponsors a clinical conference to review and update guidelines for the diagnosis and management of NF1 and NF2.
1992	The NF Foundation forms the International Neurofibromatosis Association in Luxembourg.
1993	Scientists identify the NF2 gene and describe its protein product.	26,27
	The NF Foundation establishes an international network of clinics to improve diagnosis and treatment of people with NF1 and NF2
1994	The first multicenter clinical trials are launched to test new therapies for people with NF.
1995	Direct gene testing becomes available for NF1 and NF2. (The tests are available only in the research setting, for reasons discussed in Chapter 2.)
1997	The NF Foundation Clinical Care Advisory Board leads a worldwide effort to provide an updated consensus about diagnostic and management criteria for NF1 and NF2.	11
1990 to present	Researchers advance knowledge of how the NF1 and NF2 gene mutations contribute to these disorders’ manifestations, including tumor formation and cognitive difficulties.	28
	Researchers establish that schwannomatosis is genetically distinct from NF2 and consensus builds that it represents a third form of neurofibromatosis.

The man who is most responsible for synthesizing these various observations and case reports was a German professor of pathology, Friedrich Daniel von Recklinghausen (Fig. 1–2), who in 1882 coined the term neurofibroma (from “neuro” for nerve and “fibroma” for fibrous tissue). In his landmark monograph, On Multiple Fibromas of the Skin and Their Relationship to Multiple Neuromas, von Recklinghausen also was the first to realize that tumors common in this disorder arose from cells that help to form the protective myelin sheath around nerves. In recognition of his contributions, what is now known as NF1 was first called “von Recklinghausen’s disease.” As clues continued to accumulate into the 20th century, additional manifestations were associated with the disorder, such as café-au-lait spots, Lisch nodules, skeletal abnormalities, and rare malignancies.