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Dermatologic Manifestations of Neurofibromatosis Type 1

  • Author: Matthew F Helm; Chief Editor: Dirk M Elston, MD  more...
 
Updated: May 24, 2016
 

Overview

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.

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Presentation

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.[1] 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.)

A light-brown hyperpigmented lesion is noted on th A light-brown hyperpigmented lesion is noted on the arm and has a smooth border. Most persons affected by neurofibromatosis type 1 have such café-au-lait macules.
Neurofibromas are noted on the right arm and right Neurofibromas are noted on the right arm and right chest in association with a café-au-lait macule on the arm. The association of these lesions is a useful clue to the diagnosis of neurofibromatosis type 1.
The café au lait macules of neurofibromatosis have The café au lait macules of neurofibromatosis have an even tan color and a smooth border. The presence of neurofibromas in the upper right corner of the photo as well as the lower left corner make a diagnosis of neurofibromatosis almost certain.

Axillary freckling

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.

Axillary freckling is also known as the Crowe sign Axillary freckling is also known as the Crowe sign. This pigmentary change is seen in about one third of individuals affected with neurofibromatosis type 1, but it can also be seen in several other conditions.

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.)

Neurofibromas increase in number and size over tim Neurofibromas increase in number and size over time. Soft pedunculated neurofibromas are shown here on the arm of a woman with neurofibromatosis type 1.
Neurofibromas are soft on palpation, and they may Neurofibromas are soft on palpation, and they may exhibit a buttonhole sign, whereby they can be pushed deeper into the dermis.
Neurofibromas are often pedunculated and are compo Neurofibromas are often pedunculated and are composed of spindled cells with wavy nuclei embedded in an acidophilic stroma. (Hematoxylin and Eosin stained sections; original magnification 20x).

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.[2]

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.[3] See the histology images below.

Neurofibromas are composed of delicate spindle cel Neurofibromas are composed of delicate spindle cells in a loose stroma. (Hematoxylin and Eosin; original magnification 400x)
Schwannomas (neurilemmomas) are benign tumors that Schwannomas (neurilemmomas) are benign tumors that develop along the course of nerves. Spindle cells may cluster in "stacks" that create palisades. Two adjacenet stacks with intervening Schwann cell cytoplasm are know as Verocay bodies. (Hematoxylin and eosin stained sections; original magnification 200x).
Schwannomas have areas with spindle shaped schwan Schwannomas have areas with spindle shaped schwan cells (Antoni A areas) and intervening stroma (Antoni B areas). (Hematoxylin and eosin stain; original magnification 400x)
Sheets of spindled cells are depicted in this mali Sheets of spindled cells are depicted in this malignant schwannoma. Malignant degeneration should be expected in a painful or rapidly enlarging tumor in any patient with neurofibromatosis.
High-power view of a malignant schwannoma reveals High-power view of a malignant schwannoma reveals sheets of hyperchromatic spindle cells with pleomorphic nuclei.
Granular cell tumors are also known as granular ce Granular cell tumors are also known as granular cell schwannomas. They often involve the mouth but may occur anywhere on the skin or in the soft tissues. Tumor cells are polygonal and have unique eosinophilic granules in the cytoplasm. (hematoxylin and eosin stained sections; original magnification 400x).

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.[4] 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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Contributor Information and Disclosures
Author

Matthew F Helm State University of New York Upstate Medical University

Disclosure: Nothing to disclose.

Coauthor(s)

Michael R Nazareth, MD, PhD President and Board Certified Dermatologist, Western New York Dermatology, PLLC

Michael R Nazareth, MD, PhD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, Medical Society of the State of New York, Society for Pediatric Dermatology

Disclosure: Received honoraria from Galderma for speaking and teaching.

Specialty Editor Board

David F Butler, MD Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

David F Butler, MD is a member of the following medical societies: American Medical Association, Alpha Omega Alpha, Association of Military Dermatologists, American Academy of Dermatology, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Phi Beta Kappa

Disclosure: Nothing to disclose.

Edward F Chan, MD Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Edward F Chan, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Ponciano D Cruz, Jr, MD Professor and Vice-Chair, Paul R Bergstresser Chair, Department of Dermatology, University of Texas Southwestern Medical Center

Ponciano D Cruz, Jr, MD is a member of the following medical societies: Texas Medical Association

Disclosure: Received consulting fee from RCTS for independent contractor; Received honoraria from Mary Kay Cosmetics for consulting; Received grant/research funds from Galderma for principal investigator.

Acknowledgements

Jennifer Kam Ray, MD Staff Physician, Southtowns Radiology Associates

Disclosure: Nothing to disclose.

References
  1. DeBella K, Szudek J, Friedman JM. Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics. 2000 Mar. 105(3 Pt 1):608-14. [Medline].

  2. Pasmant E, Ortonne N, Rittié L, et al. Differential expression of CCN1/CYR61, CCN3/NOV, CCN4/WISP1, and CCN5/WISP2 in neurofibromatosis type 1 tumorigenesis. J Neuropathol Exp Neurol. 2010 Jan. 69(1):60-9. [Medline].

  3. Hivelin M, Wolkenstein P, Lepage C, Valeyrie-Allanore L, Meningaud JP, Lantieri L. Facial aesthetic unit remodeling procedure for neurofibromatosis type 1 hemifacial hypertrophy: report on 33 consecutive adult patients. Plast Reconstr Surg. 2010 Apr. 125(4):1197-207. [Medline].

  4. Gutmann DH. Eliminating barriers to personalized medicine: learning from neurofibromatosis type 1. Neurology. 2014 Jul 29. 83(5):463-71. [Medline].

 
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The café au lait macules of neurofibromatosis have an even tan color and a smooth border. The presence of neurofibromas in the upper right corner of the photo as well as the lower left corner make a diagnosis of neurofibromatosis almost certain.
Neurofibromas increase in number and size over time. Soft pedunculated neurofibromas are shown here on the arm of a woman with neurofibromatosis type 1.
Neurofibromas are soft on palpation, and they may exhibit a buttonhole sign, whereby they can be pushed deeper into the dermis.
Neurofibromas are often pedunculated and are composed of spindled cells with wavy nuclei embedded in an acidophilic stroma. (Hematoxylin and Eosin stained sections; original magnification 20x).
Neurofibromas are composed of delicate spindle cells in a loose stroma. (Hematoxylin and Eosin; original magnification 400x)
Schwannomas (neurilemmomas) are benign tumors that develop along the course of nerves. Spindle cells may cluster in "stacks" that create palisades. Two adjacenet stacks with intervening Schwann cell cytoplasm are know as Verocay bodies. (Hematoxylin and eosin stained sections; original magnification 200x).
Schwannomas have areas with spindle shaped schwan cells (Antoni A areas) and intervening stroma (Antoni B areas). (Hematoxylin and eosin stain; original magnification 400x)
Sheets of spindled cells are depicted in this malignant schwannoma. Malignant degeneration should be expected in a painful or rapidly enlarging tumor in any patient with neurofibromatosis.
High-power view of a malignant schwannoma reveals sheets of hyperchromatic spindle cells with pleomorphic nuclei.
Granular cell tumors are also known as granular cell schwannomas. They often involve the mouth but may occur anywhere on the skin or in the soft tissues. Tumor cells are polygonal and have unique eosinophilic granules in the cytoplasm. (hematoxylin and eosin stained sections; original magnification 400x).
A light-brown hyperpigmented lesion is noted on the arm and has a smooth border. Most persons affected by neurofibromatosis type 1 have such café-au-lait macules.
Neurofibromas are noted on the right arm and right chest in association with a café-au-lait macule on the arm. The association of these lesions is a useful clue to the diagnosis of neurofibromatosis type 1.
Axillary freckling is also known as the Crowe sign. This pigmentary change is seen in about one third of individuals affected with neurofibromatosis type 1, but it can also be seen in several other conditions.
 
 
 
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