Case Based Pediatrics For Medical Students and Residents
Department of Pediatrics, University of Hawaii John A. Burns School of Medicine
Chapter XVIII.11. Neurofibromatosis
Vince K. Yamashiroya, MD
August 2002

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A 6 month old infant female is seen in your office as a new patient for a well baby visit. Her family moved from here from Asia recently, where she was born. There were no prenatal or postnatal complications, and she has had no significant medical problems since birth. Her family history is positive for her father who has a condition in which his body is covered with fleshy small growths, similar to skin tags, and on the father's side, there are several family members with the same warty growths, seizures, and high blood pressure.

Exam: VS are normal. Her growth parameters are in the 25-50th percentiles. Her examination is otherwise unremarkable except for multiple coffee colored spots on her trunk and abdomen.

You suspect neurofibromatosis based on her cutaneous findings and the family history. You schedule her for a follow up visit tomorrow to discuss this further. You have overnight to prepare yourself to initiate a proper evaluation and treatment plan, and to counsel the family.


Neurofibromatosis is one of the more common types of neurocutaneous syndromes that is well known because of its clinical features. Its hallmark sign is the neurofibroma, which is a tumor of nerve connective tissue (1). There are actually two types of neurofibromatosis. The first type is NF-1, which is the most common type and its clinical features include cafe au lait spots and neurofibromas. The second type, NF-2, only accounts for 10% of the cases of neurofibromatosis, and its clinical feature is bilateral vestibular schwannomas (or acoustic neuromas), with cafe au lait spots and skin neurofibromas being less common (2). Neurofibromatosis was recognized as a disease for well over a hundred years. In 1882, Friedrich von Recklinghausen published his famous monograph describing this entity, and this disease became known as von Recklinghausen disease, which is NF-1. Other people have also recognized this disease as early as the eighteenth century, such as Tilesius and Akenside. In 1981, Dr. Vincent Riccardi recognized NF-2 as a clinically distinct entity from NF-1 (3).

Today, we know much more about both types of neurofibromatosis. Through molecular genetic studies, it was discovered in 1990 that the NF-1 gene is on the long arm of chromosome 17 and encodes for a protein called neurofibromin. It is believed that perhaps the NF-1 gene is a tumor suppressor gene, and that neurofibromin allows for the dephosphorylation of ras-GTP to ras-GDP. In patients with NF-1, there is a mutation in the NF-1 gene, therefore ras, which is thought to be a proto-oncogene, is not dephosphorylated and sends intracellular signals to inhibit apoptosis (programmed cell death) and stimulate cellular proliferation (4). The NF-2 gene was discovered in 1987 to be in the long arm of chromosome 22, and in the 1990's, its gene product was determined to be in the band 4.1 families of proteins that are associated with the cytoskeleton; however the function of the NF-2 gene is still not known (5).

We do know that both types of neurofibromatosis are autosomal dominant, just like tuberous sclerosis, which is another type of neurocutaneous syndrome. Interestingly, new mutations occur in about 50% of patients with NF-1 (6) and NF-2 (7), making these gene loci one of the highest known mutation sites in humans.

NF-1 is one of the most common types of neurocutaneous syndromes, with an incidence of 1/4000 (2). There is no sex or ethnic predilection (8). NF-2, on the other hand, is uncommon, having an incidence of about 1 in 40,000 births (7). This type of neurofibromatosis usually presents later in life, and is therefore seen by internists, rather than pediatricians.

The diagnosis of NF-1 is still a clinical one, despite the recognition of the gene causing NF-1 and its gene product. In 1987, the U.S National Institutes of Health Consensus Development Conference developed a list of criteria for the diagnosis of this disease. NF-1 is present in a patient who has two or more of the following signs:

1. Six or more cafe au lait macules greater than 5 mm in greatest diameter in prepubertal individuals or >15 mm in greatest diameter after puberty.

2. Two or more neurofibromas of any type or one or more plexiform neurofibromas (see definition below).

3. Freckling in the axillae or inguinal region (Crowe sign).

4. A tumor in the optic pathway.

5. Two or more Lisch nodules (iris hamartomas).

6. A distinctive osseous lesion, such as sphenoid wing dysplasia or thinning of the cortex of the long bones (with or without pseudoarthrosis).

7. A first degree relative (parent, sibling, or offspring) with NF-1 by the above criteria.

The signs of NF are age-dependent, with more signs appearing at older ages. Because of this, about 90% of children who are older than six years of age can be diagnosed using these criteria, but younger children may be missed (9).

Neurofibromas are benign tumors arising from large and small nerves, and are a cardinal feature of neurofibromatosis. They are mainly composed of Schwann cells and fibroblasts, and can occur anywhere in the body outside of the brain and spinal cord proper. There are four different types of neurofibromas: discrete cutaneous neurofibromas, discrete subcutaneous neurofibromas, deep nodular neurofibromas, and diffuse plexiform neurofibromas. The cutaneous neurofibromas are sessile or pedunculated masses on the skin, which are fleshy and non-tender, and can vary in size. The subcutaneous neurofibromas lie deeper and look like bumps on the skin, which can sometimes be tender. The deep nodular neurofibromas involve tissues and organs underneath the dermis, and resemble cutaneous and subcutaneous neurofibromas. The diffuse plexiform neurofibromas differ from the others in that it has fronds that penetrate normal tissue, making them difficult to remove. These plexiform neurofibromas can vary in severity from no skin involvement to severe disfigurement, sometimes resulting in elephantiasis with limb hypertrophy or severe facial disfigurement. The deep nodular neurofibromas and diffuse plexiform neurofibromas share a common feature in that they can become malignant peripheral nerve sheath tumors. The single most important sign that a tumor has become malignant is persistent, unexplained pain. Neurofibromas can occur at any time of life, although the cutaneous, subcutaneous, and deep nodular types usually appear in late childhood to early adolescence, and sometimes later. The number and size of the neurofibromas increase throughout middle and late adulthood. By 16 years of age, all patients will have cutaneous and/or subcutaneous neurofibromas. The ones that occur earlier in life are the diffuse plexiform neurofibromas, which are actually thought to be congenital. An interesting finding is an abnormal hair whorl over the spine, called the Riccardi sign, which represents a congenital paraspinal plexiform neurofibroma, which can lead to dysplastic scoliosis later in life (8,10).

Cafe au lait spots are spots with the color of coffee with milk, being tan colored. They can vary in size from smaller than 10 mm to as big as covering a body part on one side, although the typical lesions are 1-3 cm ovoid spots, which are uniform in color. They can occur anywhere on the body except for the scalp, eyebrows, palms, and soles. Histologically, they are giant melanosomes within melanocytes. Although they are a hallmark feature of NF-1 and occur in almost all individuals with this disease, they can also be seen in normal individuals as well. They are usually one of the first signs that will alert the clinician to the presence of NF-1 since they usually appear at the time of birth (11).

Axillary freckling is akin to cafe au lait spots except they are smaller, about 1 to 3 mm in size, and occur in clusters. They usually appear in intertriginous areas like the axillae, inguinal area, upper eyelids, the base of the neck, breast folds in women, and skin folds in obese patients.

Lisch nodules are another characteristic finding of NF-1 occurring more frequently as an affected individual ages. In those who are 5 years old, the frequency is 25%, at age 10 years it is 50%, and by age 20 years it is more than 95%. They are pigmented hamartomas appearing as translucent masses with a gray-tan hue due to the melanin-containing cells that are on the iris. Usually they are bilateral and do not affect vision. Lisch nodules are diagnostic for NF-1, and they can be seen on slit-lamp examination by an ophthalmologist.

Optic gliomas are benign tumors which can form anywhere along the optic tract from the globe all the way to the optic radiations out of the occipital lobe. They occur in about 15% of NF-1 patients, but only 33% of these are symptomatic. These symptoms include decreased visual acuity, visual field deficits, proptosis, strabismus, optic atrophy, headache, nausea, anorexia, hypothalamic dysfunction, and precocious puberty. Current recommendations are for patients to have a full ophthalmologic examination when first diagnosed with NF; follow-up full ophthalmologic examination annually up to age 6 years; tests for visual acuity, color vision (Ishihara test), and slit-lamp examinations at 8, 13, and 20 years of age; and full ophthalmologic examinations at 10, 16, and 25 years of age. If a tumor is suspected, then neuroimaging is indicated. If an optic glioma is asymptomatic, then it can be observed. However, if it becomes progressive or symptomatic, then surgery, medical, or radiation therapy should be considered.

Neurofibromatosis should be considered a multiorgan disease in that tumors can occur in any part of the body. Other manifestations are hypertension from renal artery stenosis, seizures, scoliosis, long bone dysplasia, sphenoid bone dysplasia, short stature, macrocephaly, and peripheral nerve sheath malignant tumors. Mental retardation is not common (about 5%), while learning disabilities are more common (30-60%).

The diagnosis of NF-2 is based on criteria that were first developed in 1987 by the NIH. The Clinical Care Committee of the National Neurofibromatosis Foundation later revised this in 1997, the criteria of which is seen below (7):

Definite NF-2: Bilateral vestibular schwannomas (VS) or family history of NF-2 (first-degree relative) plus: 1) Unilateral VS (<30 years of age), or 2) Any two of the following: meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacities.

Presumptive or Probable NF-2: Unilateral VS (<30 years of age) plus at least one of the following: meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacities. Or multiple meningiomas (two or more) plus unilateral VS (<30 years of age) or one of the following: glioma, schwannoma, juvenile posterior subcapsular lenticular opacities.

The vestibular schwannoma, previously known as the acoustic neuroma, is the hallmark tumor of NF-2. This tumor arises from the vestibular branch of cranial nerve VIII, and is universal in patients with this type of neurofibromatosis (12). Although this tumor arises from the vestibular branch, the patient usually notices hearing problems before vestibular problems (e.g., balance). The average age of onset is 18 to 22 years, although it ranges from 10 years to over 35 years of age. The patient may first present with hearing problems, such as when using the telephone. The onset is gradual, although sometimes it can occur suddenly. Besides tinnitus and deafness, other signs and symptoms include facial weakness, visual problems, and painful peripheral nerve tumors. Children present differently from adults in that they show manifestations not involving cranial nerve VIII. These include spinal cord compression by gliomas or meningiomas, and ophthalmologic problems such as cataracts, strabismus, and amblyopia (7).

Cafe au lait spots can be a sign of neurofibromatosis or a part of other neurocutaneous syndromes. The following is a list of diseases that involve cafe au lait spots:

1. McCune Albright syndrome
2. Tuberous sclerosis
3. Fanconi anemia
4. Bloom syndrome
5. Ataxia telangiectasia
6. Russell-Silver syndrome
7. Multiple lentigines (LEOPARD) syndrome
8. Multiple endocrine neoplasia type 2b
9. Bannayan-Riley-Ruvalcaba syndrome

Solitary cafe au lait spots are commonly seen in the healthy population, although three or more spots can be seen in 0.2 to 0.3% of normal children, and six or more spots in less than 0.1% of healthy children. To suspect NF-1, there should be six or more cafe au lait spots that are larger than 0.5 cm in prepubertal patients, and larger than 1.5 cm in postpubertal patients. These spots are not a major feature of NF-2, and these patients may have only a few spots present. McCune Albright syndrome includes precocious puberty and multiple endocrine problems. The cafe au lait spots are often large and irregular. It has been compared to having the shape of the coast of Maine, compared to the smooth shape of NF, which is likened to the coast of California.

Tuberous sclerosis (TS) is discussed in a separate chapter. Although cafe au lait spots are not as common as the hypopigmented macules in TS, they can be present. These spots can be seen in 25% of patients with Fanconi anemia, which presents with aplastic anemia, mental retardation, generalized hyperpigmentation, radial ray defects, eye anomalies, and other multiorgan problems. NF patients, unlike Fanconi anemia, do not have anemia. Bloom syndrome is an autosomal recessive disorder that features areas of hypo and hyperpigmentation, prenatal and postnatal growth retardation, thin triangular facies, telangiectatic rash in sun exposed areas, and malignancies (leukemia, breast, and gastrointestinal). Ataxia telangiectasia can also have cafe au lait spots, but probably only in a minority of patients. This disease includes progressive neurodegeneration, bulbar conjunctival telangiectasia, immunodeficiency, and increased risk for malignancies. Russell Silver dwarfism can also have cafe au lait spots but some studies report that it might not be different in frequency to the normal population. This disorder includes prenatal growth retardation, small triangular facies, and short and curved fifth fingers.

The management of a patient with neurofibromatosis should focus on genetic counseling and evaluating for the development of new tumors. The patient should be referred to a neurofibromatosis clinic if one is available, because of the multidisciplinary assistance that can be received. Blood pressure should be obtained at every visit because of the higher risk for hypertension. Those with scoliosis should be referred to an orthopedist for treatment. Learning disabilities can occur and the patient should be evaluated for this annually in terms of his or her academic performance. Dermal neurofibromas can be removed surgically or by laser. Annual eye examinations should be performed annually for the first six years of life, with less frequent examinations thereafter. Prenatal diagnosis is available for NF-1 by amniocentesis or chorionic villus sampling, and can be performed if one of the parents has NF. However, NF is of variable severity, therefore, the value of determining whether a fetus has NF is controversial (9).

The management of NF-2 includes genetic counseling, annual hearing screenings, and surgery for tumors. Because of the risk for deafness, learning sign language and wearing hearing aids should be considered (7).

The prognosis for NF-1 is not a promising one. Throughout life, these individuals develop more lesions, with new types of tumors such as Lisch nodules, neurofibromas, and optic gliomas appearing. A feature of neurofibromatosis is its clinical variability, so it is difficult to determine who will be having severe, debilitating, and disfiguring disease. However, the life expectancy for NF-1 patients is reduced in general, with most deaths occurring in childhood or middle adulthood. Deaths in childhood are usually caused by an intracranial tumor, however, a malignant peripheral nerve sheath tumor, leukemia, or an embryonal tumor can be the cause as well. Sometimes, death can also be due to the growth of a plexiform neurofibroma in the cervical to upper mediastinum region. Deaths in middle adulthood are due to a malignant peripheral nerve sheath tumor or sarcoma from another type of tissue. Other causes are acute hydrocephalus, severe seizures, gastrointestinal hemorrhage, intracranial hemorrhage due to vasculopathy, progressive spinal cord encroachment by plexiform neurofibromas or unstable dysplastic scoliosis, and complications of hypertension due to arterial dysplasia or pheochromocytoma.

NF-2 patients do not fare well either. The average life expectancy is 36 years with death being due to surgically inoperable tumors. These patients also suffer from vision and hearing deterioration, chronic pain from tumors, and loss of ambulation.

We have now identified the gene and gene products for neurofibromatosis. With new discoveries and technologies, gene therapy may be used to treat and prevent this disease in individuals at risk in the near future.


Questions

1. How many cafe au lait spots are needed to diagnose neurofibromatosis? How big do they need to be in prepubertal and postpubertal patients?

2. What is the hallmark tumor in NF-2? How is it manifested in a patient?

3. If you see a patient with cafe au lait spots who you suspect has von Recklinghausen's disease, what tests or evaluations need to be performed?

4. What types of neurofibromas can become malignant?

5. What skin manifestations occur in the newborn period? How about in older children and adults?

6. What is the genetic inheritance pattern for neurofibromatosis? What percentage of cases occur without a family history of NF (sporadic)?

7. What are the eye tumors that you can find on the iris of NF-1 patients called?


References

1. Davis FA. Taber's Cyclopedic Medical Dictionary, 16th edition. 1989, Philadelphia: F.A. Davis Company, p. 1203.

2. Haslam RHA. Chapter 605.1 Neurofibromatosis. In: Behrman RE, et al (eds). Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: W.B. Saunders Company, pp. 1835-1836.

3. Riccardi VM. Chapter 1 - Historical Background and Introduction. In: Friedman JM, et al (eds). Neurofibromatosis, 3rd edition. 1999, Baltimore: The Johns Hopkins University Press, pp. 1-25.

4. Viskochil DH. Chapter 5 - The Structure and Function of the NF1 Gene: Molecular Pathophysiology. In: Friedman JM, et al (eds). Neurofibromatosis, 3rd edition. 1999, Baltimore: The Johns Hopkins University Press, pp. 119-141.

5. MacCollin M, Gusella J. Chapter 15 - Molecular Biology. In: Friedman JM, et al (eds). Neurofibromatosis, 3rd edition. 1999, Baltimore: The Johns Hopkins University Press, pp. 351-362.

6. Friedman JM. Chapter 4 - Clinical Genetics. In: Friedman JM, et al (eds). Neurofibromatosis, 3rd edition. 1999, Baltimore: The Johns Hopkins University Press, pp. 110-118.

7. MacCollin M. Chapter 13 - Clinical Aspects. In: Friedman JM, et al (eds). Neurofibromatosis, 3rd edition. 1999, Baltimore: The Johns Hopkins University Press, pp. 299-326.

8. Friedman JM, Riccardi VM. Chapter 2 - Clinical and Epidemiological Features. In: Friedman JM, et al (eds). Neurofibromatosis, 3rd edition. 1999, Baltimore: The Johns Hopkins University Press, pp. 29-86.

9. Friedman JM. Chapter 3 - Evaluation and Management. In: Friedman JM, et al (eds). Neurofibromatosis, 3rd edition. 1999, Baltimore: The Johns Hopkins University Press, pp. 87-109.

10. Korf BR. Chapter 6 - Neurofibromas and Malignant Tumors of the Peripheral Nerve Sheath. In: Friedman JM, et al (eds). Neurofibromatosis, 3rd edition. 1999, Baltimore: The Johns Hopkins University Press, pp. 142-161.

11. Tekin M, Bodurtha JN, Riccardi VM. Cafe au Lait Spots: The Pediatrician's Perspective. Pediatr Rev 2001;22(3):82-89.

12. MacCollin M, Stemmer-Rachamimov A. Chapter 14 - Associated Tumors. In: Friedman JM, et al (eds). Neurofibromatosis, 3rd edition. 1999, Baltimore: The Johns Hopkins University Press, pp. 327-350.


Answers to questions

1. 6 spots. >5 mm in prepubertal and >15 mm in postpubertal patients.

2. Vestibular schwannoma (acoustic neuroma). It is manifested by hearing problems.

3. Blood pressure measurements and eye examinations.

4. Deep nodular neurofibromas and diffuse plexiform neurofibromas.

5. Cafe au lait spots in newborn period. Discrete cutaneous and subcutaneous neurofibromas, axillary freckling in the older patient.

6. Autosomal dominant. 50% occur without a family history.

7. Lisch nodules.


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