C h a p t e r 6
Genetic and Congenital Disorders
109
There are at least two genetically and clinically distinct
forms of the disorder: type 1 NF (NF-1), also known as
von Recklinghausen disease
, and type 2 bilateral acoustic
NF (NF-2). Both of these disorders result from a genetic
defect in a tumor-suppressor gene that regulates cell dif-
ferentiation and growth. The gene for NF-1 has been
mapped to chromosome 17 and the gene for NF-2 to
chromosome 22.
3
Type 1 NF is a relatively common disorder, with a fre-
quency of 1 in 3500.
3
Approximately 50% of cases have a
family history of autosomal dominant transmission, and
the remaining 50% appear to represent a new mutation.
The disorder is characterized by multiple neural tumors
(neurofibromas) dispersed anywhere on the body; numer-
ous pigmented skin lesions, some of which are café au
lait spots; and pigmented nodules (Lisch nodules) of the
iris.
7–11
The cutaneous neurofibromas, which vary in
number from a few to many hundreds, manifest as soft,
pedunculated lesions that project from the skin. They are
the most common type of lesion, often are not apparent
until puberty, and are present in greatest density over
the trunk (Fig. 6-3). The subcutaneous lesions grow just
below the skin; they are firm and round, and may be pain-
ful. Plexiform neurofibromas involve the larger peripheral
nerves. They tend to form large tumors that cause severe
disfigurement of the face, overgrowth of an extremity, or
skeletal deformities such as scoliosis. Pigmented nodules
of the iris (Lisch nodules), which are specific to NF-1, usu-
ally are present after 6 years of age. They do not pres-
ent any clinical problem but are useful in establishing a
diagnosis.
A second major component of NF-1 is the presence of
large (usually
≥
15 mm in diameter), flat cutaneous pig-
mentations, known as
café au lait spots
. They are usu-
ally a uniform light brown in whites and darker brown
in persons of color, with sharply demarcated edges.
Although small single lesions may be found in normal
children, larger lesions or six or more spots larger than
1.5 cm in diameter suggest NF-1. The skin pigmenta-
tions become more evident with age as the melanosomes
in the epidermal cells accumulate melanin.
Children with NF-1 are also susceptible to neuro-
logic complications. There is an increased incidence
of learning disabilities, attention deficit disorders, and
abnormalities of speech. Complex partial and general-
ized tonic-clonic seizures are a frequent complication.
Neurofibromatosis-1 is also associated with increased
incidence of other neurogenic tumors, including menin-
giomas, optic gliomas, and pheochromocytomas.
2
FIGURE 6-3.
Neurofibromatosis, type I. Multiple cutaneous
neurofibromas are noted on the face and trunk. (From Peiper S,
Rubin DS. In: Rubin R, Strayer DS, eds. Rubin’s Pathology:
Clinicopathologic Foundations of Medicine. 6th ed. Philadelphia,
PA: Wolters Kluwer Health/Lippincott Williams &Wilkins;
2012:238.)
Lens dislocation,
myopia
Pectus carinatum
(pigeon chest),
pectus excavatum
(funnel chest)
Vertebral deformity
(kyphosis, scoliosis)
Long arms,
arm span
exceeds height
EYE
SKELETAL DEFORMITY
CARDIOVASCULAR
Joint
hypermobility,
especially
fingers, wrists,
and knees
Aortic
aneurysm,
floppy valves
Dissecting aortic
aneurysm with
exsanguination
FIGURE 6-2.
Clinical features of Marfan syndrome.
