21 45. Somoano B, Tsao H.

Genodermatoses with cutane-

ous tumors and internal malignancies. Dermatol Clin.
2008;26(1):69-87, viii.
46. Jaju PD, Ransohoff KJ, Tang JY, et al. Familial skin cancer
syndromes: increased risk of nonmelanotic skin can-
cers and extracutaneous tumors. J Am Acad Dermatol.
2016;74(3):437-451; quiz 452-434.
47. El Khoury J, Khalifeh I, Kibbi AG, et al. Cutaneous
metastasis: clinicopathological study of 72 patients
from a tertiary care center in Lebanon. Int J Dermatol.
2014;53(2):147-158.
Part 21
::
Metabolic, Genetic, and Systemic Diseases
48. Fernandez-Anton Martinez MC, Parra-Blanco V, Aviles
Izquierdo JA, et al. Cutaneous metastases of internal
tumors. Actas Dermosifiliogr. 2013;104(10):841-853.
49. Wagner G, Fenchel K, Back W, et al. Leukemia cutis-
epidemiology, clinical presentation, and differential
diagnoses. J Dtsch Dermatol Ges. 2012;10(1):27-36.
50. Oluwole OO, Zic JA, Douds JJ, et al. Cutaneous manifes-
tations and management of hematologic neoplasms.
Semin Oncol. 2016;43(3):370-383.

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 Chapter 135 :: The Neurofibromatoses
:: Robert Listernick & Joel Charrow
AT-A-GLANCE
■ Autosomal dominant condition with incidence of 1
in 3000 live births.
■ Diagnosed clinically if 2 major features are present
(see Table 135-1).
■ Cutaneous neurofibromas:
■ Softer than the surrounding connective tissue
and protrude just above the skin surface
or lie just under the skin with an overlying
violaceous hue.
■ Subcutaneous neurofibromas:
■ Arise from peripheral nerves, both under the
skin and deep in the viscera.
■ Generally much harder.
■ Plexiform neurofibromas:
■ Generally present at birth or apparent during
the first several years of life.
■ May lead to disfigurement, blindness
(secondary to amblyopia, glaucoma, or
proptosis), loss of limb function, or organ
dysfunction by compression of vital structures.
■ Mosaic neurofibromatosis Type 1 (segmental NF-1):
■ Manifestations of NF-1, usually limited to one
area of the body.
■ Occurs as result of a postconceptional mutation
in the NF1 gene, leading to somatic mosaicism.
CLINICAL FEATURES
A consensus development conference was held by the
National Institutes of Health in 1987 to establish diag-
nostic criteria to promote better clinical research and
care of patients with neurofibromatosis Type 1 (NF-1).1
The 7 diagnostic features recognized at this confer-
ence (Table 135-1), and the recommendation that 2 or
more of these 7 features be present before a diagnosis
of NF-1 is established, have proven extremely useful
and continue to be used without modification more
than 30 years later. Perhaps the one caveat is the iden-
tification of a separate autosomal dominant syndrome
caused by an inactivating mutation of the gene encod-
ing sprouty-related EVH1 domain-containing pro-
tein 1 (SPRED1), which leads to the development of
café-au-lait spots, intertriginous freckling, and macro-
cephaly, but none of the other manifestations of NF-1
(Legius syndrome).2
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21
CAFÉ-AU-LAIT SPOTS
Café-au-lait spots, which are flat, pigmented macules,
are often the first manifestation of NF-1 to appear
(Fig. 135-1). Frequently present at birth, they become
more numerous as the infant grows; new ones may
continue to appear throughout the first decade of life.
Chapter 135 :: The Neurofibromatoses
Once noticed, they tend to grow in size in proportion to
the overall growth of the child. Although infrequently
found on the face, they may be noted anywhere on the
body. The size, shape, and contour of café-au-lait spots
are of no diagnostic significance, and the oft-quoted
adage about smooth-edged café-au-lait spots being
more typical of NF-1 rather than McCune-Albright
syndrome is incorrect. When café-au-lait spots over-
lap each other, the area of overlap may be darker than
either individual spot. When found within slate grey
macules, they are typically surrounded by a more
lightly pigmented halo. Individuals with large num-
bers of café-au-lait spots do not have “more-severe”
NF-1, and the location of the macules in no way pre-
dicts the location of subsequent neurofibromas.
Café-au-lait spots represent collections of heavily
pigmented melanocytes of neural crest origin in the
epidermis. Although the cells may contain increased
numbers of “giant” melanosomes, or melanin macro-
globules, these are not unique to NF-1, and their pres-
ence or absence in biopsies is not helpful diagnostically.
INTERTRIGINOUS
FRECKLING
Café-au-lait spots smaller than 5 mm are referred to
as freckles, and are commonly present in the axillae,
inguinal region, and under the breasts (Fig. 135-2).
Unlike ordinary freckles in these locations, these
lesions are not related to sun exposure, and are consid-
ered virtually pathognomonic of NF-1 (Crowe sign).
Of all children ultimately diagnosed with NF-1, 81%
will have intertriginous freckling by age 6 years.3
DISCRETE
NEUROFIBROMAS
Neurofibromas, which consist of Schwann cells, mast
cells, fibroblasts, and perineural cells, are benign
nerve sheath tumors that appear as discrete masses
08/12/18 4:19 pm
21 TABLE 135-1
Diagnostic Criteria for Neurofibromatosis Type 1a
■ Six or more café-au-lait macules larger than 5 mm in greatest
diameter in prepubertal individuals, and larger than 15 mm in
greatest diameter in postpubertal individuals.
■ Two or more neurofibromas of any type or 1 plexiform
neurofibroma.
■ Freckling in the axillary or inguinal regions.
■ Optic glioma.
■ Two or more iris Lisch nodules.
■ A distinctive osseous lesion such as sphenoid dysplasia or thinning
of long bone cortex with or without pseudarthrosis.
■ A first-degree relative (parent, sibling, or offspring) with neurofibro-
matosis Type 1 by the above criteria.
Part 21

a
Patient must meet 2 or more of the listed criteria for diagnosis.
::

arising from peripheral nerves.4 Cutaneous neuro-

Metabolic, Genetic, and Systemic Diseases

fibromas protrude just above the skin surface or lie

just under the skin with an overlying violaceous hue
(Fig. 135-3). They are softer than the surrounding
connective tissue, often creating a “buttonholing” sen-
sation when a finger is rubbed gently over the surface
(Fig. 135-4). Subcutaneous neurofibromas that arise
from peripheral nerves, both under the skin and deep
in the viscera, are generally much harder (Fig. 135-5). If
they arise from the dorsal root ganglia, they may grow Figure 135-2 Axillary freckling.
through neural foramina, compressing the spinal cord,
creating a “dumbbell” appearance. Subcutaneous neu-
rofibromas in the neck may feel like a “beaded neck-
lace,” often being confused with lymph nodes. While
fewer than 20% of children younger than 10 years of
age have cutaneous neurofibromas, neurofibromas
generally start appearing after puberty and increase
in number as the patient grows older. Women who
have NF-1 often comment on the appearance of cuta-
neous neurofibromas during pregnancy. The majority
of adult patients with NF-1 probably have numerous

2466 Figure 135-3 Cutaneous neurofibromas with overlying

Figure 135-1 Café-au-lait spots. hyperpigmentation.

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