92

NEUROFIBROMATOSIS

NEUROFIBROMATOSIS
T E King Jr, San Francisco General Hospital, San
Francisco, CA, USA
A C Zamora, Hospital Universitario Dr Jose E
Gonzalez, Monterrey Nuevo Leon, Mexico
& 2006 Elsevier Ltd. All rights reserved.

Abstract
Neurofibromatosis (NF) is a relatively common autosomal
dominant genetic disorder characterized by neurological and
cutaneous lesions. NF-1 (von Recklinghausens disease) accounts for approximately 85% of the patients and it is this form
that is most likely to demonstrate lung involvement. Respiratory
involvement occurs in 1015% of patients with NF, most commonly in adults. The thorax and lungs can be affected in several
ways: cutaneous and subcutaneous neurofibromas on the chest
wall that can overlay the lung and appear as lung nodules;
kyphoscoliosis; ribbon deformity of the ribs; thoracic neoplasms; diffuse interstitial fibrosis; or bullae.

Introduction
Neurofibromatosis (NF) is a relatively common disorder characterized by neurological and cutaneous
lesions. There are two major forms: type 1 (NF-1, von
Recklinghausens disease) and NF-2 (formerly known
as bilateral acoustic NF or central NF) (Table 1).
NF-1 accounts for approximately 85% of the patients
and its prevalence in the population is 1 in 5000. In
3050% of cases of NF-1 there is no family history;
these sporadic cases probably arise from (usually paternal) germ cell mutations. NF-2 is the less common
form affecting about 1 in 40 000 persons, with a
prevalence within the population of 1 in 210 000.
Sporadic gene mutations occur in 50% of cases. NF-2
is characterized by bilateral tumors on the eighth
cranial nerve, which cause progressive hearing loss.

Cutaneous lesions are the result of the maldevelopment of neural crest cells. The number of dermal
neurofibromas varies from individual to individual.
Large plexiform neurofibromas develop along peripheral nerves and involve deeper tissues. Extracutaneous
(visceral) involvement may not be apparent during life
unless such lesions produce symptoms. In NF-1, the
thorax and lungs can be affected in several ways: cutaneous and subcutaneous neurofibromas on the chest
wall that can overlay the lung and appear as lung nodules; kyphoscoliosis; ribbon deformity of the ribs; thoracic neoplasms; diffuse interstitial fibrosis; or bullae.

Pathology
Neurofibromas are hamartomatous in nature and of
multicellular origin; they are composed mostly of
Schwann cells, but also contain fibroblasts, mast
cells, and macrophages. Vascular histologic changes
in NF are commonly described in six types (intimal,
advanced intimal, nodular-aneurysmal, periarterial,
epithelioid-cell, and pericapillary). Immunohistochemical and electron microscopic observations suggest a smooth muscle cell origin of proliferating
spindle-shaped cells. The histopathologic findings in
the lung are described below.

Clinical Features
NF is extremely variable in its symptoms, signs, intensity, and progression. There is no discrimination
in its sexual, racial, ethnic, or national distribution.
Table 2 provides the diagnostic criteria for NF-1.
These criteria are both highly specific and sensitive in
all but the youngest children. The following features
confirm a diagnosis of NF-2: bilateral vestibular

Table 1 Classification of neurofibromatosis

Variable

Neurofibromatosis type 1

Neurofibromatosis type 2

Inheritance
Penetrance
Incidence
Prevalence
Features

Autosomal dominant
Complete
1/2600 to 1/4000
1/5000
Neurofibromas, cafe-au-lait macules, learning
disabilities, skeletal dysplasia
NF-1 chromosome 17q11.2
Neurofibromin
GTPase activating protein

Autosomal dominant
Complete
1/40 000
1/210 000
Vestibular schwannomas, other schwannomas,
meningiomas, ependymomas, cataracts
NF-2 chromosome 22
Merlin or schwannomin
Cytoskeletal protein

Gene
Protein
Function

Adapted from Korf BR, Henson JW, and Stemmer-Rachamimov A (2005) Case 13-2005 a 48-year-old man with weakness of the limbs
and multiple tumors of spinal nerves. New England Journal of Medicine 352: 18001808.

NEUROFIBROMATOSIS 93
Table 2 Diagnostic criteria for neurofibromatosis type 1
At least two of the following clinical features must be present:
1. Six or more cafe-au-lait spots/macules

45 mm in prepubertal patients

415 mm in postpubertal patients
2. Two or more neurofibromas of any type or one plexiform
neurofibroma
3. Skin fold freckle (groin, axilla, and neck base)
4. Optic glioma (detected by magnetic resonance imaging)
5. Lisch nodules (X2 iris hamartomas)
6. Skeletal dysplasia: a distinctive bony lesion such as sphenoid
dysplasia or thinning of the long bone cortex with or without
psuedoarthrosis
7. Family history: a first degree relative (parent, sibling, or
offspring) with NF-1 based upon the above criteria
Adapted from National Institutes of Health Consensus Development Conference (1988) Neurofibromatosis: conference
statement. Archives of Neurology 45: 575578 and Korf BR, Henson JW, and Stemmer-Rachamimov A (2005) Case 13-2005 a
48-year-old man with weakness of the limbs and multiple tumors
of spinal nerves. New England Journal of Medicine 352:
18001808.

schwannomas or family history of NF-2 (first degree

relative) plus either unilateral vestibular schwannoma in patients o30 years old or any two of the
following: meningioma, glioma, schwannoma, and
juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract.
General Features

The typical order of appearance of clinical features is

cafe-au-lait spots, axillary freckling, Lisch nodules,
and neurofibromas (Figure 1). Cafe-au-lait spots are
present in 99% of the patients. They may be difficult
to distinguish in individuals of African descent.
Freckling occurs in areas of skin apposition, especially the axillary and groin areas. Freckling is usually not apparent at birth but often appears during
early childhood. Neurofibromas are characteristic
tumors of NF that grow especially during puberty
and pregnancy. They almost always involve the skin,

(a)

(b)

(c)

(d)

Figure 1 (a) Cafe-au-lait spots: flat; uniformly hyperpigmented macules that range in size from 1 to 60 mm and vary in number from at
least six to hundreds. Reproduced from http://www.nfinc.org/what.shtml Neurofibromatosis, Inc., PO Box 18246, Minneapolis, MN
55418, with permission. (b) Neurofibromas: cutaneous neurofibromas are benign and do not carry an increased risk of developing
malignant transformation. However, they often represent a major cosmetic problem in adults. (c) Lisch nodules in iris: bilateral, welldefined, dome-shaped, gelatinous elevations from the iris surface, ranging from clear to yellow or brown in color. (d) Freckles in skin fold
of axilla. Reproduced from http://www.nfinc.org/what.shtml Neurofibromatosis, Inc., PO Box 18246, Minneapolis, MN 55418, with
permission.

94

NEUROFIBROMATOSIS

but they may occur in deeper peripheral nerves

and nerve roots and in or on viscera and blood
vessels innervated by the autonomic nervous system.
Multiple cranial nerves may be involved resulting in
facial weakness or numbness, visual or auditory disturbances. The tumors may be painful or tender under pressure. Lisch nodules are pigmented iris
hamartomas that are present in 94% of patients
6 years old or older. Bony abnormalities include
pseudoarthrosis (or false joint), bone dysplasia, short
stature (13% have a height 2 standard deviations
below the population mean), and scoliosis (1025%
of affected individuals). Neurologic disorders include
seizures and neuroimaging abnormalities. Macrocephaly is a common feature. Approximately 40
60% of children with NF-1 manifest below average
performance on standardized IQ tests and demonstrate problems with reading, writing, and use of
numbers. NF patients rarely have mental retardation.
Systemic arterial hypertension is a frequent finding in
adults with NF-1 and may develop during childhood.
NF is associated with an increased incidence of
malignancy, ranging from malignant tumors of the
central nervous system to Wilms tumor, rhabdomyosarcoma, juvenile chronic myeloid leukemia,
and pheochromocytoma. The most common are
central nervous system neoplasms (e.g., astrocytomas
and brainstem gliomas) and optic pathway gliomas.

Thoracic Involvement

Table 3 lists diseases such as upper airway, chest

wall, mediastinal, thoracic neoplasms, and lung
parenchyma.

Table 3 Thoracic manifestations of neurofibromatosis

Upper airway
Tracheal neurogenous tumors
Laryngeal neurogenous tumors
Chest wall
Subcutaneous neurofibromas
Kyphoscoliosis
Rib notching (inferior) from intercostal neurofibroma
Apical neurofibroma (Pancoasts syndrome)
Mediastinal
Neurogenic tumors
Plexiform neurofibroma
Meningocele
Vegal nerve neurofibroma
Thoracic neoplasms
Malignant degeneration of neurofibromas
Metastatic neural tumor
Lung parenchyma
Bullous lung disease
Interstitial lung disease

Upper airway An estimated 5% of patients with

NF-1 have an intraoral manifestation of the disease.
Discrete neurofibromas may involve the tongue, the
larynx, or occur in the cervical region where large
tumors of the parapharyngeal space may result in
distortion of the airway. These lesions may cause
obstruction, and symptoms of dyspnea, stridor, loss
or change of voice, or dysphagia. Tracheal and endotracheal neurofibromas are rare. Hoarseness may result from recurrent laryngeal nerve involvement. It
has been suggested that radiographic examination of
the neck be performed before anesthesia in these patients in order to examine the upper airway and to
avoid spinal cord damage during laryngoscopy and
tracheal intubation.
Thoracic cage Rib abnormalities are common in
patients with NF. They have been described as
twisted ribbon deformity. Notching of the ribs occurs secondary to erosion by intercostal neurofibromas or a primary defect in bone formation.
Vertebral abnormalities Scoliosis is common and
occurs in 1058% of patients with NF. It typically
involves the lower cervical and upper thoracic spine
in children aged 515 years of age, and there is no
sex predilection. Although scoliosis is often associated with paravertebral neurofibromas, it is not clear
whether the tumors themselves are the cause of the
vertebral column distortion. Other possible causes of
spinal deformity in NF include osteomalacia, a localized neurofibromatous tumor eroding and infiltrating bone and mesodermal dysplasia.
Thoracic neoplasms Cutaneous and subcutaneous
neurofibromas on the chest wall can overlay the lung
and appear as lung nodules. On the other hand, primary or secondary malignancy in the lung has been
overlooked because of confusion caused by overlying
cutaneous lesions on X-rays. In 5% of patients, the
neurofibromas in NF undergo transformation to malignant degeneration and commonly metastasize to
the lungs.
Neurofibromas may be found in virtually any location including the mediastinum and account
for about 1020% of primary mediastinal masses in
adults (Figure 2). One-third of patients with neurofibromas have NF. Neurofibromas arise from
peripheral nerves and nerve sheath. The radiograph
features are a round, elliptical, or lobulated paravertebral mass, often one or two interspaces in length.
Neurogenic neoplasms that arise in the intercostal
nerves can be associated with rib destruction and a
chest wall mass. Paraspinal neurofibromas may grow

NEUROFIBROMATOSIS 95

Figure 2 Neurofibroma: mediastinal mass. Photo courtesy of W

R Webb, Department of Radiology, University of California  San
Francisco.

to an enormous size, giving rise to the classic thoracic

dumbbell tumor (Figure 3).
Plexiform neurofibromas are the hallmark lesion
of NF-1. These occur in 30% of NF-1 patients, are
usually congenital, and affect long portions of
the nerve involved; infiltration of the nerve itself
and the surrounding tissue may occur, giving rise to
extensive disfiguration. Plexiform neurofibromas are
multiple and lobulated, have ill-defined margins with
mediastinal fat, and surround great vessels with loss
of normally visible fat planes. They can mimic the
appearance of extensive mediastinal lymph node enlargement (Figure 4). Malignant progression occurs
in 216% of patients and is the major cause of morbidity and mortality in NF-1.
Meningocele Intrathoracic meningocele has been
associated with NF (64% of cases). It represents
anomalous herniation of the spinal meninges through
an intervertebral foramen or a defect in the vertebral
body. It is slightly more common on the right side.
Meningocele commonly presents as an incidental
finding (60%) or with dyspnea (23%). On chest radiographs, a meningocele is a sharply marginated
paravertebral soft tissue mass associated with scoliosis or rib and vertebral defects at the same levels.
On computed tomography (CT), it has low attenuation because it contains cerebrospinal fluid.
Pulmonary vascular involvement NF can involve
vessels throughout the body, such as the retinal,
lumbar, mesenteric, renal, and both the intracranial
and extracranial arteries. The incidence of vascular
lesions has been reported to be 3.6%. Involvement of

Figure 3 Paraspinal neurofibromas. Coronal T1-weighted MRI

showing large dumbbell neurofibroma in T2/T3 intervertebral foramen and occupying the apex of the left thoracic cavity and displacing the spinal cord to the right. Reproduced from Hirsch NP,
Murphy A, and Radcliffe JJ, Neurofibromatosis: clinical presentations and anaesthetic implications, British Journal of Anaesthesia, 2001, 86, 555564, & The Board of Management
and Trustees of the British Journal of Anaesthesia. Reproduced
by permission of Oxford University Press/British Journal of
Anaesthesia.

Figure 4 Plexiform neurofibromas in NF. Mediastinal widening

(large arrows) reflects the presence of multiple neurofibromas
along the courses of mediastinal nerves. Extensive intercostals
neurofibromas (small arrows) mimic pleural thickening. Photo
courtesy of W R Webb, Department of Radiology, University of
California  San Francisco.

the pulmonary artery has been reported in a patient

with severe pulmonary hypertension.
Hemothorax Spontaneous hemothorax occurs
more frequently in women and is most often
found on the left side. The intercostal artery and
the subclavian artery are the most common ruptured

96

NEUROFIBROMATOSIS

arteries. Biopsy results reveal neurofibromatous invasion of the vessel wall. The prognosis is poor (50%
survival) especially when the blood loss is massive.
The recommended treatment is immediate exploratory thoracotomy and ligation, bypass, or replacement of the affected vessel.
Diaphragmatic paralysis Involvement of the phrenic nerves, both central (posterior fossa tumor) or
peripheral root nerves, by NF has occasionally
caused diaphragmatic paralysis.
Parenchymal abnormalities Diffuse parenchymal
lung disease has an incidence of between 10% and
33% among patients with NF. The number of affected men appears to outnumber affected women
but this may be explained by the fact that the largest
number of cases comes from studies on patients from
Veterans Administration Hospitals. Diffuse interstitial fibrosis and bullae, either alone or in combination, are the best described pulmonary parenchymal
lesions.

Figure 5 Chest radiograph shows large lung volumes with upper lobe hyperlucency (right greater than the left) and a reticular
pattern predominant at the lung bases. Photo courtesy of W R
Webb, Department of Radiology, University of California  San
Francisco.

Clinical features NF is usually diagnosed years before the appearance of lung disease. Age at diagnosis
ranges from 23 to 72 years with a mean of 50 years
for studies. In most patients, the finding of lung disease was incidental, but dyspnea on exertion was
the most common complaint. There are no apparent
abnormal physical signs on examination. Coexisting
NF and pulmonary fibrosis has been reported in a
mother and son, but a familial predisposition is rare.
Pulmonary function test Generally, lung function
testing shows an obstructive pattern, but a restrictive
defect may be dominant. A decreased diffusion capacity (DLCO) and hypoxemia can be seen.
Radiographic findings Bullous lung disease may
occur alone or in combination with diffuse interstitial lung disease. The interstitial changes are usually
diffuse, bilateral, basal, and subpleural (Figure 5).
Large apical asymmetric thin-walled bullae sometimes occupy a major portion of the hemithorax associated with areas of hypovascularity (Figure 6).
Classical honeycombing is rare. Diminished perfusion and ventilation to apices of the lungs have been
documented by radionuclide studies in a patient with
cutaneous NF.
Histopathological findings The pulmonary parenchymal disease is attributed to a mesenchymal defect
resulting in primary deposition of collagen. Ultrastructural studies have shown fragmentation of collagen fibers in the lung. The pathologic features of

Figure 6 High-resolution computed tomography (HRCT) shows

cysts and bullae often indistinguishable from emphysema. Photo
courtesy of W R Webb, Department of Radiology, University of
California  San Francisco.

the pulmonary parenchymal lesions, at autopsy or

lung biopsy, revealed areas of relatively normal lung
alternated with patchy interstitial fibrosis, thickening, and cellularity of the alveolar septa. The findings
appear similar to those found in non-specific interstitial pneumonia rather than usual interstitial pneumonia. In more advanced stages, the lesions show
more severe fibrosis and obliteration of alveoli and
blood vessels with honeycombing.
Complications Interstitial lung disease in NF may
be severe enough to result in cor pulmonale. Scar

NEUROFIBROMATOSIS 97

carcinoma can develop, especially if the patient is a

smoker.

Pathogenesis
NF-1 is an autosomal dominant genetic disorder
with an incidence of approximately 1 in 2600 to 1 in
4000 individuals (Table 1). Up to 50% of cases are
spontaneous. The gene is found on chromosome 17,
which functions as a tumor suppressor predisposing
to the development of cancer. Mutations at the NF-1
gene result in diminished levels of neurofibromin
with resultant development of the wide variety of
tumors seen in the disease. The pathogenesis of the
pulmonary process remains ill defined.

Animal Models
A number of approaches have been taken to develop
models for the tumors seen in individuals affected
with NF-1. Initial studies focused on the generation of
mice with a targeted mutation in the NF-1 gene. Second-generation models included NF-1  /  chimeric
mice and NF-1 exon-specific knockout mice. Recently,
tissue-specific inactivation of NF-1 has yielded important insights into the function of neurofibromin in
specific cell types and the consequence of NF-1 loss on
tumorigenesis in NF-1. Similar approaches have been
taken for the study of NF-2.
Pathologic analyses of a transgenic murine model
for NF-2 demonstrated a high incidence of Schwann
cell-derived tumors and Schwann cell hyperplasia.
This model has been shown to develop spontaneous
schwannomas detected by magnetic resonance
imaging (MRI). Transgenic mice (Nf1 /  ) lacking
neurofibromin expression in astrocytes have been
developed to closely mimic NF-1. They develop optic
nerve and optic chiasm low-grade fibrillary astrocytomas, which resemble their human counterparts in some respects but lack the characteristic
microcystic spaces, Rosenthal fibers, and granular
bodies.

Management and Current Therapy

Genetic counseling is the only preventive approach to
NF. No specific treatment is available for the pulmonary parenchymal lung disease.
See also: Genetics: Overview. Interstitial Lung Disease: Overview. Oncogenes and Proto-Oncogenes:

Overview. Transgenic Models. Tuberous Sclerosis.

Tumors, Malignant: Overview.

Further Reading
Bourgouin PM, Shepard JO, Moore EH, et al. (1988) Plexiform
neurofibromatosis of the mediastinum: CT appearance. American Journal of J Roentgenology 151: 461463.
Casselman ES and Mandell GA (1979) Vertebral scalloping in
neurofibromatosis. Radiology 131: 8994.
Casselman ES, Miller WT, Shu Ren L, et al. (1977) von
Recklinghausens disease: incidence of roentgenographic findings with a clinical review of the literature. CRC Critical Review
of Diagnostic Imaging 9: 387419.
Chaglassian JH, Riseborough EJ, and Hall JE (1976) Neurofibromatous scoliosis. Natural history and results of treatment in
thirty-seven cases. Journal of Bone and Joint Surgery of America
58: 695702.
Dolynchuk KN, Teskey J, and West M (1990) Intrathoracic meningocele associated with neurofibromatosis: case report. Neurosurgery 27: 485487.
Friedman JM and Birch PH (1997) Type 1 neurofibromatosis: a
descriptive analysis of the disorder in 1,728 patients. American
Journal of Medical Genetics 70: 138143.
Gutmann DH and Giovannini M (2002) Mouse models of
neurofibromatosis 1 and 2. Neoplasia 4: 279290.
Hirsch NP, Murphy A, and Radcliffe JJ (2001) Neurofibromatosis:
clinical presentations and anaesthetic implications. British Journal of Anaesthesia 86: 555564.
Israel-Asselain R, Chebat J, Sors C, et al. (1965) Diffuse interstitial
pulmonary fibrosis in a mother and son with von Recklinghausens disease. Thorax 20: 153157.
Klatte EC, Franken EA, and Smith JA (1976) The radiographic
spectrum in neurofibromatosis. Seminars in Roentgenology 11:
1733.
Korf BR, Henson JW, and Stemmer-Rachamimov A (2005) Case
13-2005 A 48-year-old man with weakness of the limbs and
multiple tumors of spinal nerves. New England Journal of Medicine 352: 18001808.
Massaro D and Katz S (1966) Fibrosing alveolitis: its
occurrence, roentgenographic and pathologic features in
von Recklinghausens neurofibromatosis. American Review of
Respiratory Diseases 93: 934942.
Massaro D, Katz S, Matthews MJ, et al. (1965) von Recklinghausens neurofibromatosis associated with cystic lung disease.
American Journal of Medicine 38: 233240.
National Institutes of Health Consensus Development Conference
(1988) Neurofibromatosis: conference statement. Archives of
Neurology 45: 575578.
Riccardi VM (1981) von Recklinghausen neurofibromatosis. New
England Journal of Medicine 305: 16171627.
Ryu JH, Parambil JG, McGrann PS, and Aughenbaugh GL (2005)
Lack of evidence for an association between neurofibromatosis
and pulmonary fibrosis. Chest 128: 23812386.
Samuels N, Berkman N, Milgalter E, et al. (1999) Pulmonary
hypertension secondary to neurofibromatosis: intimal fibrosis
versus thromboembolism. Thorax 54: 858859.
Webb WR and Goodman PC (1977) Fibrosing alveolitis in patients
with neurofibromatosis. Radiology 122: 289293.