Dermatologic Manifestations of Neurofibromatosis Type 1
- Author: Matthew F Helm; Chief Editor: Dirk M Elston, MD more...
Type 1 neurofibromatosis has a variable phenotypic expression that includes dermatologic manifestations. Some patients may have a primarily cutaneous expression, while others may have life-threatening or severely disfiguring complications.
Neurofibromatosis is an autosomal dominant disorder that affects the bone, nervous system, soft tissue, and skin. At least 8 different clinical phenotypes of neurofibromatosis have been identified, and they are linked to at least 2 genetic disorders. Clinical manifestations increase over time. Neurologic problems and malignancy development may supervene.
A neurocutaneous condition, neurofibromatosis can involve almost any organ system. Thus, the presenting signs and symptoms may vary widely. Two major subtypes exist: type 1 neurofibromatosis, also known as von Recklinghausen neurofibromatosis, which is the most common subtype and is referred to as peripheral neurofibromatosis, and type 2 neurofibromatosis, which is referred to as central neurofibromatosis. These descriptions are not especially accurate, because type 1 neurofibromatosis often has central features. This article will examine the dermatologic manifestations of type 1 neurofibromatosis.
Neurofibromatosis is often diagnosed because of unusual pigmentary patterns. Café au lait macules—irregularly shaped, evenly pigmented, brown macules—are often present at birth, but they increase in number during the first few years of life. Neurofibromas form in late adolescence, most commonly in the skin. Patients may report cutaneous discoloration or disfigurement or more serious physical symptoms (eg, pain caused by neurofibromas, pathologic fractures, hypertensive headaches due to pheochromocytoma).
Café au lait spots
Most individuals with neurofibromatosis have 6 or more café au lait spots that are 1.5 cm or greater in diameter. In young children, 5 or more café au lait macules greater than 0.5 cm in diameter are suggestive of neurofibromatosis, and further diagnostic workup should be pursued. Less than 1% of healthy children have 3 or more such spots, although 1 or 2 café au lait macules are commonly encountered in healthy individuals without disease. (See the images below.)
Axillary freckling (as well as freckling on the perineum), known as the Crowe sign, is a helpful diagnostic feature in neurofibromatosis (see the image below). Axillary freckling and inguinal freckling often develop during puberty. The development of freckles often follows the development of café au lait macules, but it precedes the development of neurofibromas. Eighty percent of type 1 neurofibromatosis patients have freckling of the axillae. Areas of freckling and regions of hypertrichosis occasionally overlay plexiform neurofibromas.
Neurofibromas are the most common benign tumor of type 1 neurofibromatosis. These tumors are composed of Schwann cells, fibroblasts, mast cells, and vascular components. They can develop at any point along a nerve. Three subtypes of neurofibroma exist: cutaneous, subcutaneous, and plexiform. Cutaneous lesions and subcutaneous lesions are circumscribed; neither is specific for type 1 neurofibromatosis. These nodules may be brown, pink, or skin colored. They may be soft or firm to the touch, and they may have the pathognomonic buttonhole invagination when pressed with a finger. (See the images below.)
Plexiform neurofibromas are noncircumscribed, thick, and irregular, and they can cause disfigurement by entwining important supportive structures. The plexiform subtype is specific for type 1 neurofibromatosis.
Although neurofibromas are most common tumor associated with type 1 neurofibromatosis, other neural tumors such as schwannomas, granular cell tumors, and malignant peripheral nerve sheath tumors may be encountered. See the histology images below.
Abnormalities in the neurofibromin gene in the pericentromeric region of chromosome 17 are associated with type I neurofibromatosis. Microarray analysis has identified both up- and down-regulation of multiple genes that play a role in tumorigenesis.
Extensive facial tumors may lead to hemifacial hypertrophy, which can be mitigated by facial aesthetic unit remodeling.
Exciting work is being done to look at how personalized medicine may be used to treat various aspects of neurofibromatosis type 1. Next-generation sequencing has identified low-grade optic gliomas that exhibit NF1 gene inactivation and exhibit changes in PTEN and BRAF gene function. These findings suggest that subsets of patients may be identified for specific interventional therapies in the near future.
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