ot Ricky A. Alaniz OD and Andrew S.
Gurwood OD, FAAO
Neurofibromatosis (NF-1):
von Ricklinhausen’s disease
Neurofibromatosis (NF-1) describes a
variety of related syndromes
characterised by neuroectodermal
tumours arising within multiple organs.
The unique features of the disease may
include familial history, skin blemishes
(café-au-lait spots), neurofibromas,
optic nerve glioma and iris lesions
(Lisch nodules). While the treatment is
dependant on the findings, ocular
management is infrequently required1-15.
Figure 1 Café-au-lait spots
Figure 2 Lisch nodules on the iris
Figure 3 Skin neurofibromas
38 April 5, 2002 OT
Case study
A 14-year old black female was referred
to our practice by her primary care
physician to rule out the need for
additional testing or the presence of
ocular complications for recently
diagnosed neurofibromatosis type 1 (NF-
1). She presented without visual or
ocular complaints and was otherwise in
good health. Observation of the skin
uncovered multiple neurofibromas and
café-au-lait blemishes.
Uncorrected visual acuities measured
20/20 at distance and near, both eyes.
Extraocular muscles motilities, colour
vision, stereoacuity and confrontational
visual fields were normal, with no
evidence of afferent pupillary defect.
Refraction revealed clinical emmetropia,
both eyes. Biomicroscopy and gonioscopy
demonstrated normal and healthy
anterior segment structures, with Lisch
nodules noted on the anterior stroma of
both irides. Goldmann applanation
tonometry measured 17mmHg, both eyes.
Dilated fundus evaluation was
unremarkable, both eyes.
Since she had been diagnosed and
tested previously by her general
physician and because no ocular
abnormalities were uncovered (angle
structures were normal, intraocular
pressures measured within the normal
range and no fundus abnormalities were
present), no additional testing was
recommended. The patient was scheduled
for follow-up on an annual basis.
Discussion
The term von Recklinghausen’s
neurofibromatosis recognises Clause Von
Recklinghausen, who first reported a
constellation of findings associating the
variances of a disease consisting of
tumours, which originated from the
fibrous connective tissue sheaths of small
nerves1-15. Virchow was the first to
describe a familial inheritance pattern
and work by Preiser and Davenport
confirmed that inheritance was
autosomal dominant3,4.
Von Recklinghausen’s
neurofibromatosis (also termed
neurofibromatosis type 1 [NF-1] or
peripheral neurofibromatosis) is one of
the four clinical forms of
neurofibromatosis currently recognised2-7.
NF-1 is the most common form of the
disease, accounting for 90% of all cases2-
9
. It has a prevalence of between one in
3,000 and one in 5,0005,6, with its gene
having a penetrance that is virtually
100%8. There is no predilection for
gender or race5,6.
Bolande13 defined neurofibromatosis
as a neurocristopathy (disease of neural
crest origin). The neural crest is a
transient embryonic structure composed
of cells of which migrate to various body
parts to form neuronal, neural-
supportive, pigmentary, endocrine or
other tissues13. The precise mechanisms
of the disease’s expression remain under
investigation. Significant arrays of
tissues, which develop from neural-crest
derivatives, make it impossible to tie the
origin of Von Recklinghausen’s
neurofibromatosis to a single chemical,
immunologic or cellular marker13.
Researchers have postulated that the
study of neural-crest migration and
differentiation holds the key to
understanding the pathogenesis of the
condition7,8,13,14.
The main diagnostic features of von
Recklinghausen’s neurofibromatosis are
café-au-lait spots (FFigure 1), axillary
and inguinal freckling and Lisch nodules
of the iris. Neurofibromas, plexiform
neurofibromas, optic nerve gliomas,
distinctive osseous lesions and family
history are also hallmarks1-7,10-15.
Café-au-lait spots are found in
virtually all NF-1 patients1,6,9,10. They are
small, brown patches visible on the skin,
which are composed of epidermal
melanocytes with giant pigment
granules. These hyperpigmented spots
increase in size and number through the
third decade, but decrease in number
later in life10.
Lisch nodules are melanocytic
hamartomas (abnormal proliferations of
tissue normally forming in the region)
found within the iris9-12. They appear as
light brown nodules on the iris stroma
(FFigure 2). Lisch nodules are rarely
present at birth and develop in almost
all affected persons by the second or
third decade of life9-12.
Neurofibromas are benign tumours
consisting predominately of Schwann
cells and fibroblasts. Endothelial cells,
perineural cells and mast cells are also
present4,5. They typically involve the skin,
but may be situated adjacent to
peripheral nerves, blood vessels or
within viscera13. Cutaneous lesions are
the most common and develop in 100%
of all affected patients by the age of
165,6.
Plexiform neurofibromas appear as
large, ill-defined, soft subcutaneous
swellings, usually evident at birth,
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Table 1 Diagnostic criteria for NF-1
1. Five or more café-au-lait spots more than 5mm in diameter in pre-pubertal patients;
six or more café-au-lait spots more than 15mm in diameter in post-pubertal patients
2. Two or more neurofibromas of any type, or one plexiform neurofibroma
3. Axillary or inguinal freckling
4. Optic glioma
5. Two or more Lisch nodules
6. A distinctive osseous lesion (pseudoarthrosis of the tibia or sphenoid wing dysplasia)
7. A first-degree relative diagnosed with NF-1 in accordance with the above criteria
resulting from the diffuse thickening of
nerve trunks located in the orbital or
temporal region of the face6,7. These
lesions are benign but have the potential
to cause cosmetic and visual
disturbances if they involve the
orbit6,7(FFigure 3). Plexiform
neurofibromas occur in approximately
one third of NF-1 cases6,7.
Optic gliomas are benign tumours,
which consist of glial cells and mucinous
material. With an incidence of 10-70%,
optic gliomas account for 2-5% of all
childhood central nervous system
tumours15. Lewis et al13 reported that
30% of affected patients had unilateral
gliomas, 30% had bilateral tumours and
40% of patients had some chiasmal
involvement. Interestingly, only 20% of
the individuals identified as having
tumours reported visual symptoms5,15.
Optic nerve gliomas, while they are
usually non-progressive, have the
potential to enlarge rapidly, causing
proptosis and visual consequences15.
Patients with bilateral optic nerve
gliomas are often visually asymptomatic,
with normal or near-normal acuities15.
Patients with unilateral optic nerve
gliomas frequently display an afferent
pupillary defect, secondary to optic
nerve compression15.
The diagnostic criteria for von
Recklinghausen’s neurofibromatosis was
established by the National Institute of
Health Consensus Development
Conference (NIHC) and requires at least
two of seven listed criteria (TTable 1)9.
Differential diagnosis includes
conditions capable of blemishing the
skin, producing tumours of the skin,
orbit or CNS, conditions capable of
producing proptosis and conditions
which may produce iris freckling9-11. While
a variety of ocular diseases produce
these findings (blepharitis, chalazion,
cysts of the epidermis, Grave’s
ophthalmopathy, Fuch’s hetrochromic
iridocyclitis, Trisomy 21 (Brushfeld’s
spots), uveitis (Koeppe and Busacca
nodules), none of them produce the
distinct characteristics required by the
NIHC for definitive diagnosis9-11.
The individual course of von
www.optometry.co.uk
Recklinghausen’s neurofibromatosis
cannot be predicted2-9. Managing von
Recklinghausen’s neurofibromatosis is
difficult since there are no specific
treatments. Practitioners should focus on
the treatable elements of the disease
process7. Genetic counselling and early
detection of treatable conditions or
complications are of vital importance7
(TTable 2).
Children with von Recklinghausen’s
syndrome are susceptible to neurologic
complications. Neuroimaging of the
brain and orbit should be completed to
rule out abnormalities15. T-2 weighted
magnetic resonance imaging (MRI) is the
test of choice for detecting both
intraorbital and intracranial optic nerve
gliomas15. Visual evoked potentials are
useful for the determination of normal
or abnormal optic nerve function15. The
pattern visual evoked response is an
additional modality which is useful for
assessing chiasmal involvement15.
References
1. Von Recklinghausen, F.D. (1882)
“Uber die Multiplen Fibrome der
Haut und Ihre Beziehung zu den
Multiplen Neuromen”. A.
Hirschwald, Berlin.
2. Smith, R.W. (1849) “A Treatise on
the Pathology, Diagnosis and
Treatment of Neuroma”. Hodges and
Smith, Dublin.
Table 2
Frequently recognised complications
of NF-1
■ Plexiform neurofibromas
■ Epilepsy
■ CNS tumours
■ Spinal neurofibromas
■ Scoliosis
■ Aqueduct stenosis
■ Pseudoarthrosis of tibia and fibula
■ Gastrointestinal neurofibromas
■ Renal artery stenosis
■ Juvenile xanthogranulomas
■ Congenital glaucoma
3. Preiser, S.A. & Davenport, C.B. (1918)
“Multiple neurofibromatosis (von
Recklinghausen’s disease) and its
inheritance; with description of a
case”. American Journal of the
Medical Sciences 156: 507-540.
4. Riccardi, V.M. (1981) “Von
Recklinghausen, neurofibromatosis”.
N. Eng. J. Med. 305: 1617-22.
5. Huson, S.M., Harper, P.S. &
Compston, D.A.S. (1988) “Von
Recklinghausen neurofibromatosis : a
clinical population study in South
East Wales”. Brain 111: 1355-81.
6. Riccardi, V.M. & Eichner, J.E. (1986)
“Neurofibromatosis: Phenotype,
Natural History and Pathogenesis”.
John Hopkins University Press,
Baltimore.
7. Riccardi, V.M. & Lewis, R.A. (1988)
“Penetrance of Von Recklinghausen
neurofibromatosis: a distinction
between predecessors and
descendants”. Am. J. Hum. Genet.
42: 284-89.
8. Ledbetter, D.H., Rich, D.C., O’Connel,
P., Leppert, M. & Carey, J.C. (1989)
“Precise localization of NF I to
17q11.2 by balanced translocation”.
Am. J. Hum. Genet. 44: 20-4.
9. National Institute of Health
Consensus Development Conference,
Chicago (1988) “Neurofibromatosis”.
Arch. Neurol. 45: 575-78.
10. Crowe, F.W. & Shull, W.J. (1953)
“Diagnostic importance of Cafe-au-
lait spot in neurofibromatosis”.
Arch. Intern. Med. 91: 758-66.
11. Lewis, R.A. & Riccardi, V.M. (1981)“
von Recklinghausen
neurofibromatosis: incidence of iris
hamartoma”. Opthalmology 4 (88):
348-54.
12. Lloyd, L.A. (1973) “Gliomas of the
optic nerve and chiasm in childhood”.
Trans. Am. Ophthalmol. Soc. 71:
488-535.
13. Bolande, R.P. (1981)
“Neurofibromatosis - the
quintessential neurocristopathy:
pathogenic concepts and
relationships”. Adv. Neurol. 29: 67-75.
14. Le Douarin, N. (1980) “Migration and
differentiation of neural crest cells”.
Curr. Top. Dev. Biol. 16: 31-85.
15. Listernick, R., Charrow, J., Geenwald,
M.J. & Esterly, N.B. (1989) “Optic
Gliomas in children with
neurofibromatosis type 1”.
J. Pediatr. 114: 788-92.
About the authors
Ricky Alaniz is in private practice in
Texas. Andrew Gurwood is an Associate
Professor of Clinical Sciences at the
Pennsylvania College of Optometry in
Philadelphia.
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