Neurofibromatosis (NF) is an autosomal dominant disorder characterized
by café au lait spots and tumors of the nervous system.
NF has seven recognized subtypes:
1. NF-1: von Recklinghausen disease, mutation in NF1 gene, abnormal
2. NF-2: Acoustic neuroma, mutation in NF2 gene abnormal merlin/neurofibromin2.
6. NF-6: Café au lait macules (CALMs) only.
Synonym von Recklinghausen disease.
Age Birth: plexiform neurofibromas.
Aging from 2 to 3 years: CALM, freckling. Puberty: other neurofibromas.
Incidence NF-1, 1:3000 people;
NF-2, 1:50000 people.
Heredity AD, with variable expressivity.
NF-1 is an autosomal dominantly inherited disorder caused by
a mutation in chromosome 17q11.2. The gene product, “neurofibromin,” negatively
regulates the ras-family of signal molecules through GTP activating
protein (GAP) function. NF-2 is an autosomal dominantly inherited disorder
caused by a mutation in chromosome 22q12.2. The gene product, “merlin,” is
thought to be involved in actin cytoskeletal signaling.
CALMs are not usually present at birth but appear during the
first 3 years; neurofibromas appear during late adolescence and
may be tender to palpation. Clinical manifestations can vary depending
on which organ is affected: hypertensive headache (pheochromocytomas),
pathologic fractures (bone cysts), mental retardation, brain tumor
(astrocytoma), short stature, precocious puberty (early menses,
CALMs 2-mm to > 20-cm-brown macules
(90%) (Fig. 13-1).
Neurofibromatosis, café au
lait macules Scattered, well-demarcated uniform brown macules
>5 mm on the trunk of an infant with neurofibromatosis.
Crowe’s Sign Frecklelike
macules in the axillary or inguinal folds (80%) (Fig. 13-2).
sign Axillary freckling in an infant with neurofibromatosis.
Neurofibromas Tan nodules with “button
hole sign”—invagination with the tip of finger
(60%–90%) (Fig. 13-3).
Neurofibromatosis, neurofibromas Skin-colored
soft papules and nodules on the back are neurofibromata appearing
in late adolescence in a patient with neurofibromatosis.
Plexiform Neuromas Soft tan loose
lesions, described as a “bag of worms” (25%).
Distribution of Lesions Randomly
distributed but may be localized to one region (segmental NF).
Eye Lisch nodules (>90%),
hypertelorism (25%), glaucoma.
Musculoskeletal Macrocephaly (20%–50%),
sphenoid wing dysplasia (<5%), scoliosis (10%),
spina bifida, pseudoarthrosis (2%), thinning of long bone
cortex, local bony overgrowth, absent patellae.
Tumors Optic glioma (15%),
peripheral nerve tumors (15%), pheochromocytoma (1%),
juvenile myelomonocytic leukemia (especially in patients with JXGs),
rhabdomyosarcoma, duodenal carcinoid, somatostatinoma, parathyroid
CNS Learning disorder (50%),
seizures (5%), mental retardation (5%), hydrocephalus
Cardiovascular Hypertension (30%),
pulmonary stenosis (1%), renal artery stenosis (2%).
CALM Increased melanin within the
epidermis, increased melanocytes, giant melanosomes.
Neurofibromas Dermal small nerve
fibers with surrounding fibroblasts, Schwann cells, and perineural
Plexiform Neurofibromas Large hypertrophied
nerves with spindle-shaped fibroblasts and Schwann cells in a myxoid matrix.
Wood’s Lamp CALMs are
more easily visualized with Wood’s lamp examination.
CALMs can also be present in Albright’s syndrome (polyostotic
fibrous dysplasia). The CALMs in Albright’s syndrome frequently
have a jagged “coast of Maine” border as compared
to the CALMs in NF-1, which have smooth “coast of California” borders.
Other criteria listed above are required to establish a diagnosis
There is a variable involvement of the organs affected over time,
with NF-1 patients being most severely involved. Skin problems can
range from just a few pigmented macules to marked disfigurement
with thousands of nodules, segmental hypertrophy, and plexiform
neurofibromas. The mortality rate is higher than in the normal population,
principally because of the development of systemic tumors and complications
during adult life.
It is important to establish the diagnosis to follow patients
with a multidisciplinary approach.
NF-1 The diagnosis of NF-1 can
be made if two of the following NIH criteria are met:
1. Six or more CALMs (<5 years CALM >5 mm each,
>5 years : CALM >1.5 cm each).
2. Multiple freckles in the axillary and/or inguinal
regions (Crowe’s sign).
3. Two or more neurofibromas of any type, or one plexiform neurofibroma.
4. Bony lesion (sphenoid wing dysplasia, thinning of long bone
cortex, with or without pseudoarthrosis).
5. Optic nerve glioma(s).
6. Two or more Lisch nodules (iris hamartomas) on slit lamp examination.
7. First-degree relative (parent, sibling, or child) with NF-1
by the above criteria.
Ninety-seven percent of NF-1 patients meet these criteria by
8 years, hundred percent by 20 years. In NF-1, support groups help
with social adjustment in severely affected persons. An orthopedic physician
should manage the two major bone problems: kyphoscoliosis and tibial
bowing. The plastic surgeon can do reconstructive surgery on the
facial asymmetry. The language disorders and learning disabilities
should be evaluated by psychological assessment. Close follow-up
annually should be mandatory to detect sarcomas and leukemias.
NF-2 The diagnosis of NF-2 can
be made by:
1. CT scan or MRI demonstrating bilateral acoustic
2. A first-degree relative (parent, sibling, child) with NF-2
- a. Unilateral nerve VIII mass or
- b. Two of the following: neurofibroma, meningioma, glioma, schwannoma,
juvenile posterior subcapsular lenticular opacity.
NF-5 In NF-5, the diseaselike has
a segmental distribution because of postzygotic mutation and mosaicism.
Involvement of the gonads in these individuals can result in offspring
with full-blown NF-1, thus genetic counseling is recommended.