The neurocutaneous disorders are a group of inherited conditions associated with skin, peripheral and central nervous system (CNS), and other systemic abnormalities. Embryologically, the skin and nervous system are derived from the same neural crest origin, and thus it is not surprising that many neurologic disorders have associated skin abnormalities.

SYNONYM von Recklinghausen disease (NF Type 1).

EPIDEMIOLOGY

AGE Birth: plexiform neurofibromas may be present (25%). Aging from 2 to 3 years: CALM (>90%), axillary or inguinal freckling (80%). Puberty: other cutaneous neurofibromas (up to 90%).

GENDER M > F.

RACE All races.

INCIDENCE NF-1, 1:3,000 people; NF-2, 1:40,000 people.

HEREDITY AD, with variable expressivity.

PATHOPHYSIOLOGY

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 signaling molecules through GTP-activating protein (GAP) function. NF-2 is also an autosomal dominantly inherited disorder caused by a mutation in chromosome 22q12.2. The gene product, merlin (also known as neurofibromin 2), is thought to be involved in actin cytoskeletal signaling.

HISTORY

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 tumors (astrocytoma), short stature, or precocious puberty (early menses, clitoral hypertrophy) may develop.

PHYSICAL EXAMINATION

Skin Findings

CALMs 2-mm to >20-cm brown “coffee-with-milk” colored macules (90%). Often with an ovoid appearance (Fig. 13-1).

Crowe’s Sign Freckle-like macules in the axillary or inguinal folds (80%) (Fig. 13-2).

NEUROFIBROMAS Soft tan-to-pink nodules with “button hole sign”—invagination with the tip of finger (60–90%) (Fig. 13-3). Occasionally may be subcutaneous, below the surface of the skin.

PLEXIFORM NEUROFIBROMAS Soft tan loose lesions, described as a “bag of worms” (25%).

NEVUS ANEMICUS Patch of relatively hypopigmented-appearing skin resulting from vasoconstriction of overly sensitive cutaneous blood vessels. Seen in the neck and upper chest of individuals with NF (up to 50%).

GLOMUS TUMORS Multiple blue-red painful vascular papules on the fingers and toes, often associated with the nail bed.

JUVENILE XANTHOGRANULOMAS Yellow-orange verrucous papules with a stuck-on appearance (15%).

DISTRIBUTION OF LESIONS Randomly distributed but may be localized to one region (segmental NF).

General Findings

EYE Lisch nodules—pigmented iris hamartomas (>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%), malignant peripheral nerve sheath tumors (arise from plexiform neurofibromas) (15%), pheochromocytoma (1%), juvenile myelomonocytic leukemia (especially in patients with juvenile xanthogranulomas), rhabdomyosarcoma, duodenal carcinoid, somatostatinoma, parathyroid adenoma.

CNS Learning disorder (50%), seizures (5%), mental retardation (5%), hydrocephalus (2%).

CARDIOVASCULAR Hypertension (30%), pulmonary stenosis (1%), renal artery stenosis (2%).

LABORATORY EXAMINATIONS

Dermatopathology

CALM Increased melanin within the epidermis, increased melanocytes, giant melanosomes.

NEUROFIBROMAS Dermal small nerve fibers with surrounding fibroblasts, Schwann cells, and perineural cells.

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.

DIFFERENTIAL DIAGNOSIS

CALMs can also be present in McCune–Albright syndrome (polyostotic fibrous dysplasia). The CALMs in McCune–Albright 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 of NF.

COURSE AND PROGNOSIS

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.

MANAGEMENT

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 old: CALM >5 mm each; >5 years old: 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 age 8 years, 100% 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. A 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 and to screen for new dermatologic lesions, neurologic symptoms, or onset of hypertension. Regular ophthalmologic evaluation is also encouraged.

NF-2 The diagnosis of NF-2 can be made by:

1. CT scan or MRI demonstrating bilateral acoustic neuromas or

2. A first-degree relative (parent, sibling, child) with NF-2 and either:

   1. Unilateral nerve VIII mass or

   2. Two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity.

Cutaneous schwannomas are seen in the majority of patients with NF-2 (67%).

NF-5 In NF-5, the disease has a segmental distribution because of postzygotic mutations and mosaicism. The cutaneous lesions characteristically respect the midline. Involvement of the gonads in these individuals can result in offspring with full-blown NF-1, thus genetic counseling is recommended.