A 32-year-old woman presents to the emergency department (ED) with several flesh-colored papules on her face, trunk, and upper extremities.
She first noticed the lesions at approximately 10 years of age; however, over the past 5 years, the lesions have increased in number and become uncomfortable. She primarily complains of irritation from the lesions along her bra line. She underwent excision of similar skin lesions 5 years ago, but they have since recurred. She denies having any discharge, pain, trauma, contact with individuals with atypical skin lesions or rashes, travel out of the country, unusual exposure to animals, or a history of sexually transmitted diseases.
The patient's medical and surgical history includes environmental allergies, frequent episodes of bronchitis, and the aforementioned excisions. She has no known drug allergies, and she takes cetirizine HCl and fluticasone propionate for seasonal allergies. Her family history is significant for coronary artery disease, hypertension, diabetes mellitus, and glaucoma, but there is no family history of similar lesions. She does not smoke and only drinks alcohol on occasion. The review of her systems is otherwise unremarkable.
The physical examination reveals dozens of 0.5-2.0 cm fleshy nodules spread over her trunk, face, and upper extremities. The nodules are nontender to palpation and nonerythematous, and they produce no discharge, crusting, or scaling. Several tan oval macules measuring 1.5-3 cm in size and patches with well-defined borders are located on her trunk and upper extremities (see Images). Her vital signs are within normal limits, and her other physical findings are unremarkable.
Neurofibromatosis (NF) is an autosomal dominant disorder with numerous presentations that can affect nearly every organ system. The 2 major subtypes of NF are peripheral NF, also known as NF type 1 (NF1), and central NF, which is referred to as NF type 2 (NF2). These terms are not completely accurate, however, because NF1 also can include central nervous system (CNS) abnormalities.
About 50% of cases of NF are familial; the other 50% are caused by spontaneous gene mutation. NF1, also known as von Recklinghausen disease, is a common genetic disorder involving a mutation in the gene that produces neurofibromin on chromosome 17; the condition affects 1 in every 3000-4000 births. All races are affected, and the 2 sexes are affected equally. Two or more of the following 7 criteria must be present in order to make the diagnosis of NF1: 6 or more café-au-lait spots (irregularly shaped, evenly pigmented, brown macules), 2 or more neurofibromas, axillary or inguinal freckling, Lisch nodules (hamartomas of the iris), optic gliomas, various types of osseous lesions, and a first-degree relative with the condition.
Symptomatic NF1 typically initially manifests as café-au-lait spots that may be present at birth or that appear over time during childhood. Axillary or inguinal freckles are not usually present at birth but, rather, appear throughout childhood and adolescence. Neurofibromas are rarely seen in young children but usually appear over time in older children, adolescents, and adults. The patient may have as few as 3 or as many as thousands of these benign lesions, which consist of Schwann cells, neural fibroblasts, mast cells, and vascular elements. The neurofibromas may occur anywhere in the body and can potentially lead to marked disfigurement. If the lesions are deep, they may only be detected through palpation; cutaneous lesions may initially appear as small papules on the trunk, the extremities, the scalp, or the face. A specific type of these lesions is a plexiform neurofibroma, which is a more diffuse type of growth that can be locally invasive and quite deep. These lesions may be associated with bony erosion and pain, and they may also be accompanied by overlying hyperpigmentation or hypertrichosis. The onset of puberty or pregnancy may be associated with an increased number of neurofibromas, as well as an increase in the speed of preexisting lesion growth. Lesions along visual, auditory, or CNS nerve pathways may result in blindness, deafness, or neurologic deficits. On histology, the neurofibromas are generally well-differentiated tumors that contain elongated spindle-shaped cells and pleomorphic fibroblast-like cells. Some lesions may contain inflammatory cells. Occasionally, a large neurofibroma, a deep plexiform neurofibroma, or a peripheral nerve sheath tumor residing within the brachial or pelvic plexus may undergo malignant transformation into a neurofibrosarcoma. Unlike benign neurofibromas, neurofibrosarcomas are characteristically hypercellular, with giant cells, increased numbers of mitoses, and vascular proliferation. Additionally, small masses of malignant cells may be present within larger masses of benign cells (eg, as in a plexiform neurofibroma).
Optic nerve tumors occur primarily in children younger than 5 years. The most common presenting symptom is asymmetric, noncorrectable visual loss, but subtle peripheral field defects, optic nerve pallor, color-discrimination difficulties, or proptosis may be present without visual acuity being affected. A slow-growing optic nerve glioma (ONG) may lead to vision problems in some older children and adolescents; these patients should be monitored for visual difficulties throughout childhood and adulthood. In adults, a visually insignificant ONG may be detected incidentally on head imaging studies. Although Lisch nodules are usually not visible without use of a slit lamp, they may occasionally be seen with a direct or indirect ophthalmoscope, especially in individuals with light-colored irises. Choroidal abnormalities with a patchy appearance or retinal corkscrew vascular changes may also be noted on funduscopic examination.
Orthopedic manifestations are also commonly encountered. Congenital pseudarthrosis may be evident at birth; bowing of the tibia is the most typical presentation. Thinning and angulation of the long bones can occur throughout early childhood and adolescence, with prominence of the anterior tibia and progressive deformity; less commonly, bowing of the forearm can occur. Scoliosis with or without kyphosis may become evident in childhood or adolescence; when this finding is present in children younger than 10 years, scoliosis is associated with a poor prognosis and is likely to progress rapidly. Scoliosis detected during adolescence should still be monitored clinically, but it is much less likely to require orthopedic intervention. Sphenoid bone dysplasia is usually asymptomatic, but it can occasionally be associated with herniation through the bony defect. Other skeletal anomalies, such as fibrous dysplasia, subperiosteal bone cysts, or vertebral scalloping, can also be found.
Rare complications of NF1 include renal arterial stenosis and pheochromocytoma, either of which can present with hypertension.
NF2 is a progressive genetic disorder that is present in 1 in every 33,000-40,000 births.Patients with NF2 (which results from an abnormality on chromosome 22) typically present with acoustic neuromas or vestibular schwannomas. The clinical manifestations of NF2 include tinnitus, balance disorders, and progressive hearing loss. Affected patients may also have meningiomas, juvenile cataracts, or schwannomas of the dorsal roots of the spinal cord. The diagnosis of NF2 is based on the presence of bilateral acoustic neuromas or a unilateral acoustic neuroma in a first-degree relative with NF2.
For both NF1 and NF2, the diagnosis is primarily based on the physical findings and a positive family history. Plain radiologic studies, which may detect many bony abnormalities (such as modeling defects of the long bones or ribs, bony erosion secondary to an adjacent plexiform neurofibroma, or scoliosis), may be useful diagnostic tests. Gadolinium-enhanced magnetic resonance imaging (MRI) of the brain is the preferred diagnostic imaging study of the head, and it can be ordered either routinely—as a standard screening—or it can be ordered for patients with specific indications, such as the onset of neurologic problems or headaches. MRI studies have been shown to frequently detect unidentified bright objects in the brain parenchyma; generally, these bright spots do not enhance, they cause no mass effect, and they often resolve as the patient gets older. It has been theorized that these masses may represent benign hamartomas. MRI scanning of the brain can assist in evaluating the optic nerves or optic chiasm. This imaging modality is also useful for diagnosing and evaluating other internal lesions, such as mediastinal masses, spinal cord tumors, deep plexiform neurofibromas, neurofibromas of the brachial or sacral plexus, and abdominopelvic lesions. Genetic analyses and psychological or developmental assessments should also be part of the evaluation of patients with neurofibromas.
No cure exists for NF1 or NF2. The recommendations for follow-up include referral to support groups, psychological counseling, and evaluation for learning disorders; potential surgical excision of the lesions; and regular monitoring by a primary care provider for any lesion changes (patients with NF1 are at a somewhat increased risk for malignancy). Annual ocular examinations are recommended. Genetic testing is also available for patients with NF who wish to have children. Historically, surgery has been a successful treatment for the lesions themselves; however, there is often recurrence, and nerve damage is a risk in cases in which the lesions are located along neural pathways.