Schwannomatosis

Schwannomatosis is a newly recognized form of neurofibromatosis that is distinct from neurofibromatosis 1 (NF1) and neurofibromatosis 2 (NF2), in terms of both its primary clinical features and its genetic basis. As this book went to press, it was not yet clear what gene or mechanism might be responsible for schwannomatosis. For that reason, many basic questions about schwannomatosis remain unanswered. Research into schwannomatosis is yielding new insights every year, however. To obtain the most current information, contact the NF Foundation or visit its Web site: www.nf.org.

People with schwannomatosis develop multiple schwannomas, benign tumors of the myelin sheath that surrounds nerves, anywhere in the body except on the vestibular nerve—the chief clinical feature that differentiates it from NF2. Pain, often excruciating and sometimes disabling in intensity, is the primary symptom experienced by people with schwannomatosis and most often prompts them to seek medical help.

Schwannomatosis was once considered to be so rare that it was described mainly on the basis of “case reports,” clinical descriptions of individual patients and isolated families reported in research publications. First described in Japanese patients,¹ schwannomatosis was subsequently diagnosed in other ethnic groups around the world. Although the condition has sometimes been called “neurilemomatosis,” the accepted term today is schwannomatosis. Studies indicate that schwannomatosis is as common as NF2, although rare.^2,3

Although some researchers once argued 4 that schwannomatosis is a variant form of NF2, the consensus now is that it is a distinct type of neurofibromatosis. However, because NF2 and schwannomatosis share a key clinical feature—multiple schwannoma growth—some patients have to be followed for years until a diagnosis can be confirmed.^4–6 To further complicate matters, spinal neurofibromas associated with NF1 appear so similar to spinal schwannomas on imaging tests that the two tumor types can be distinguished only by analyzing excised tissue under a microscope. Case reports indicate that some patients with spinal tumors are inadvertently diagnosed as having NF1, when later tissue analysis indicates that they have schwannomatosis.

♦ Theories of Pathogenesis

It is not yet clear what causes schwannomatosis. Part of the challenge in finding the responsible mechanism is that the inherited or familial version of schwannomatosis accounts for only ∼15% of cases; the remainder are sporadic cases that develop without a family history of the disorder.3 This makes the hunt for the responsible gene or genes more difficult, simply because there are proportionally fewer family pedigrees and blood samples to analyze than there are for NF1 and NF2, which are inherited 50% of the time.

The hunt for the mechanism responsible for schwannomatosis has also been hindered by puzzling and contradictory findings when tumor samples were analyzed in the laboratory. For instance, both copies of the NF2 gene are inactivated in tumors taken from people with schwannomatosis, suggesting that the same mechanism seen in NF1 and NF2—a loss of a tumor suppressor gene—might be at work.⁷ As discussed in Chapter 3, when one copy of a tumor–suppressor gene is malfunctioning in all cells of the body, as it is in NF1 and NF2, then tumor formation begins after the remaining copy of a gene is lost in particular tissues. Based on analysis of tumor samples, some speculated that schwannomatosis might be caused by such a two–hit loss of the NF2 gene.⁴ Researchers have discovered, however, that both copies of the NF2 gene remain functional in healthy tissue from people with schwannomatosis, which rules out this theory.⁸

To further complicate matters, analysis of tumors from people with schwannomatosis has revealed that multiple types of genetic alterations occur on chromosome 22, usually, but not always, in the same vicinity as the NF2 gene.^7,8 This has led researchers to speculate that loss of some other tumor–suppressor gene, perhaps combined with loss of the NF2 gene, may somehow cause schwannomatosis.8 Another theory is that a structural element that makes the chromosome more susceptible to damage (or less easily repaired) may be at work. Normally chromosomes are separated and then recombined in an orderly fashion as cells divide to form new cells. A defect in this process can cause complete loss of genes or even part of a chromosome.^7,8

In light of the conflicting data, some researchers theorize that any one of several different pathological mechanisms may result in schwannomatosis. Moreover, the mechanism responsible for the familial version of the disorder may be different from the defect involved in sporadic cases. This view is supported by the fact that several other neurological disorders are caused by one or more biological defects. One example is amyotrophic lateral sclerosis (ALS or “Lou Gehrig’s” disease), which causes progressive motor deterioration. Although a gene responsible for the familial version of ALS was identified in 1993, subsequent research has shown that most sporadic cases develop because of some other biological insult, alone or in combination with others.

♦ Clinical Features

The defining clinical feature of schwannomatosis is the development of multiple schwannomas, and the dominant symptom is pain. Schwannomas are slow–growing benign tumors that do not turn malignant. Although solitary schwannomas may develop in the general population, whenever more than one such tumor develops, NF2 or schwannomatosis should be considered a possibility.

Along with other forms of neurofibromatosis, schwannomatosis is quite variable in its manifestation. There is no “typical” case. Some people develop many schwannomas; others develop only a few. Location and manifestations vary. Cranial schwannomas may be perceived as masses in the head or neck. Spinal schwannomas may cause severe pain before they are detected. Peripheral schwannomas may be clustered as masses and cause pain. Skin schwannomas may be mistaken for ordinary bumps or escape notice until diagnosis. In terms of appearance and cell type, the schwannomas associated with schwannomatosis are indistinguishable from those found in NF2 (see Chapter 10).

All people with schwannomatosis experience some degree of pain, but the intensity varies. Precise estimates of what proportion of patients experience what type of pain are hard to come by. In general, some people with schwannomatosis have such mild pain that they are never diagnosed with the disorder. Most people have significant pain, but it can be alleviated with medical or surgical treatment. In extreme but fortunately unusual cases, the pain is so severe and intractable that it is disabling. Those who endure this most severe manifestation of schwannomatosis cannot work or even function socially.

Pain can occur anywhere in the body and develops when a schwannoma enlarges, when it compresses nerve roots in the spine, or when it presses on adjacent tissue. Sometimes the pain is constant; at other times it is experienced whenever a sensitive area of the body is bumped or touched.

The pain associated with schwannomatosis is usually not accompanied by neurological deficit such as the hearing and balance losses seen in people with NF2. For this reason, the consulting physician may not immediately consider a tumor to be the cause of the pain, especially if no mass is evident upon physical examination. As a result, people with schwannomatosis typically experience pain for several years before receiving a proper diagnosis.

Neurological symptoms, however, do develop in some people with schwannomatosis. The first symptoms experienced are numbness, tingling, or weakness in the extremities. They are usually caused by a growing spinal tumor that compresses a portion of the spinal cord, but they may also be caused by a large peripheral schwannoma. Often the symptoms can be alleviated by removing the tumor surgically. Sometimes the tumor grows back or is inoperable, resulting in permanent loss of function.

One out of three people with schwannomatosis develops tumors in only one part of the body, for example, on one side of the body or in one limb.5,9 It is not yet clear whether this is a subtype or a mosaic form of schwannomatosis. In the mosaic form the genetic defect occurs during prenatal development, and therefore it governs only part of the body (see Chapter 4).

♦ Guidelines for Diagnosis

Diagnostic criteria have been proposed for schwannomatosis and are provided in Table 12–1. One challenge in diagnosis is to determine whether a person’s pain is caused by schwannoma growth or has developed for some other reason. A second challenge is to rule out other forms of neurofibromatosis. It is usually easy to distinguish schwannomatosis from NF1; ruling out NF2 may take longer. To confirm a diagnosis, it may be necessary to order a magnetic resonance imaging (MRI) scan of a suspected tumor and to analyze biopsied tissue.

**Table 12-1** Proposed Diagnostic Criteria for Schwannomatosis
Definite Schwannomatosis	Presumptive or Probable Schwannomatosis
Two or more pathologically proven schwannomas plus	Two or more pathologically proven schwannomas without symptoms of eighth nerve dysfunction when older than age 30 or
Lack of radiographic evidence of vestibular nerve tumor when older than age 18	Two or more pathologically proven schwannomas in an anatomically limited distribution (single limb or segment of spine) without symptoms of eighth nerve dysfunction, at any age

Adapted from Jacoby LB, Jones D, Davis K, et al. Molecular analysis of the NF2 tumor-suppressor gene in schwannomatosis. Am J Hum Genet 1997;61:1301, with permission.

Medical History

The medical history should include a review of the person’s overall health with special attention given to symptoms that may indicate a diagnosis of schwannomatosis. Because the presenting symptom is usually pain, many of the questions asked to establish a medical history focus on when the pain first developed, whether it is episodic or chronic, and whether it may be caused by something other than a tumor. The patient should mention any injury, illness, or infection that occurred before the pain. It is important to describe as fully as possible the pain experienced, noting the precise location in the body where it occurs. Does the pain occur in only one part of the body or are there multiple locations? Is the pain more noticeable at one time of the day? Do external factors such as light or certain foods trigger the pain? All of these questions are necessary because pain is a poorly understood phenomenon, and there are many conditions that may cause pain (see Chapter 14).

If neurofibromatosis is suspected, additional questions may be posed to help the physician decide whether the patient has NF1, NF2, or schwannomatosis. The patient should be asked about café-au-lait spots, freckling, skin bumps and tender subcutaneous masses, when these features were first noticed, and whether and how they have changed over time. Any abnormalities in vision, hearing, balance, and learning should be discussed.

Family Medical History

Schwannomatosis is a genetic disorder, but it is not yet clear which gene causes it and how the disorder is inherited. Some researchers report that schwannomatosis sometimes skips generations (known medically as incomplete penetrance).7 It is also not clear whether those people who inherit schwannomatosis experience the same manifestations as their relatives.

Given the uncertainties about the genetic transmission of schwannomatosis, it is possible that a person with multiple schwannomas may have relatives with a mild and previously undiagnosed case of schwannomatosis or even NF2. A person suspected of having schwannomatosis should be asked about the medical history of members of an extended family tree. This includes first-degree relatives (parents, siblings, children), second-degree relatives (grandparents, aunts, uncles, cousins), and more distant relations (great-grandparents, great-aunts and uncles, and descendants of second-degree relatives). If any relatives were diagnosed with NF1 or NF2, or experienced any unexplained pain or neurological symptoms, this should be noted and confirmed through medical records and direct physical examination whenever possible.

Physical Examination

The physical examination should include extra attention to the area of the body where the patient is experiencing pain. Schwannomas are encapsulated tumors, and sometimes are palpable, especially when located on peripheral nerves close to the surface of the skin. Spinal and cranial nerve schwannomas are not palpable, but may be suggested by a patient’s description of pain. Imaging studies of the related painful area may then be ordered to identify what may be causing the pain.

To rule out NF1 and NF2, the physical examination should include an assessment of features associated with both of these disorders. The skin should be examined for café-au-lait spots, freckling and neurofibromas (associated with NF1; see Chapter 5), and schwannomas (suggestive of both NF2 and schwannomatosis; see Chapter 10). The physical examination may also include basic neurological, ophthalmologic, and auditory evaluations. This might entail an assessment of balance and coordination (Chapters 5 and 10), cataracts and retinal abnormalities (Chapter 10), hearing (Chapter 10), and an examination of the eyes for Lisch nodules (Chapter 5).

Medical Tests

Currently there are no blood or genetic tests to determine whether someone has schwannomatosis. The diagnosis is confirmed with a combination of tissue analysis and imaging tests.

Pathological confirmation that a tumor is a schwannoma is established by a microscopic examination of excised tissue. Pathologically, schwannomas are homogeneous tumors because they consist predominantly of Schwann cells rather than the mix of cell types found in neurofibromas.

Cranial MRI of the eighth cranial nerve, described in Chapter 10, is a crucial step in determining correct diagnosis in someone with two or more pathologically confirmed schwannomas. If the cranial MRI reveals the presence of unilateral or bilateral vestibular schwannomas, the diagnosis is NF2. If no vestibular schwannomas are detected, follow-up screening depends on the patient’s age and other symptoms. Although the proposed diagnostic criteria for schwannomatosis suggest that cranial MRI screening can be relaxed at age 18 years,⁷ additional screening may be worthwhile inasmuch as some people develop vestibular schwannomas in their 20s and even later⁴ (see differential diagnosis below).

Spinal MRI (Figs. 12–1 and 12–2) is appropriate for anyone suspected of having schwannomatosis who is experiencing pain or numbness that might be explained by tumors pressing on nerve roots. Pain and other symptoms may result in the back or the extremities, depending on the location of the tumor.