A healthy 16-year-old girl presents with six tan patches on her trunk and upper arms, freckles in her axillae, and a reddish discoloration under the tip of her thumbnail. The tan patches have been present since birth but have enlarged over the past 4 years. She reports paroxysmal pain and cold sensitivity involving the discolored portion of her thumb. Examination reveals six tan-brown macules with smooth borders ranging from 16 to 20 mm, axillary freckling, and a tender red-blue nodule under the thumbnail.
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Neurofibromatosis type 1 (NF1, also known as von Recklinghausen disease) is the most common neurocutaneous disorder.1 It is an autosomal dominant condition with a nearly 100% penetrance and variable expressivity; it occurs due to a spontaneous mutation of the NF1 tumor suppressor gene on chromosome 17q11.2 in up to 50% of patients.1,2 NF1 encodes neurofibromin, a GTPase-activating protein that functions as a negative regulator of Ras signaling. This, in turn, stimulates the mitogen-activated protein kinase pathway, which promotes cell proliferation.1,3
The most common clinical manifestation of NF1 is café-au-lait macules (CALs), which develop in more than 99% of patients.1 CALs are well circumscribed, uniformly light to dark brown macules 2 to 5 cm in diameter, with a smooth “coast of California” border that most commonly appear on the torso, buttocks, and legs.1-3 CALs typically present at birth, increase in number and size with the growth of the child, and darken with exposure to sun.3
Other cutaneous manifestations of NF1 include Crowe sign, cutaneous neurofibromas, plexiform neurofibromas, nevus anemicus, glomus tumors, and juvenile xanthogranulomas. Crowe sign refers to the numerous 1- to 4-mm brown macules commonly found in the intertriginous areas.1 Dermal neurofibromas are benign hamartomatous tumors arising from the supporting connective tissue cells of peripheral nerves and present as dome-shaped or pedunculated, soft, rubbery papulonodules.1,2 Neurofibromas also demonstrate a characteristic “buttonhole” sign of invagination with pressure.1 Unlike cutaneous neurofibromas, which are undetectable before puberty, plexiform neurofibromas grow during early childhood, and approximately 10% undergo transformation into malignant peripheral nerve sheath tumors.1,2 Plexiform neurofibromas may present with hyperpigmentation, hypertrichosis, and thickening of the overlying skin.1 Nevus anemicus, also called hypoemic nevus, is a cutaneous anomaly typically located on the trunk, present in approximately 50% of patients with NF1. It is characterized by pale, well-defined patches with minimal vascularization after rubbing.1,4,5 Glomus tumors are benign painful tumors on the fingertips and toes that arise from the glomus body, and they occur in approximately 30% of patients with NF1.1,2 These lesions present with paroxysmal pain, intolerance to cold, localized tenderness, and an ill-defined area of reddish discoloration and swelling.1,2
Diagnosis of NF1 requires two of the seven criteria set by the National Institutes of Health (NIH), which include ≥6 CALs >5 mm in prepubertal and >15 mm in postpubertal patients; ≥2 neurofibromas or ≥1 plexiform neurofibromas; freckling in the axillae or groin; optic glioma; ≥2 Lisch nodules; sphenoid dysplasia or cortical thinning of long bones; and a first-degree relative with NF1.1 Commercially available testing can identify pathogenic NF1 mutations in >95% of nonfounder patients meeting the NIH criteria, which may aid diagnosis of NF1 in young patients who do not yet meet clinical criteria, and may suggest an alternative diagnosis in patients who meet criteria but do not have an identifiable NF1 mutation.1
The differential diagnoses include other conditions with CALs, including McCune-Albright syndrome, Noonan syndrome, DNA repair syndromes, conditions with pigmented macules that can be confused with neurofibromas, including LEOPARD (lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and deafness) syndrome, neurocutaneous melanosis, Peutz-Jeghers syndrome, mastocytoma, speckled lentiginous nevus, and conditions causing tumors that can be confused with neurofibromas, including lipomatosis, Bannayan-Riley-Ruvalcaba syndrome, and fibromatoses.1,3,6
Treatment of NF1 requires close collaboration of clinicians of multiple specialties, including neurology, pediatrics, genetics, ophthalmology, neurosurgery, plastic surgery, orthopedics, soft tissue tumor surgery, psychiatry, dermatology, radiology, and pathology, in order to facilitate a uniform approach to diagnoses and management of the condition and its complications.6 With regard to the dermatologic manifestations, treatment is not recommended for CALs or neurofibromas.6 Neurofibromas, in particular, should not be exposed to excessive heat or use of emollients, and expert advice should be sought prior to removal of plexiform neurofibromas.6
The patient in our case was diagnosed with NF1 based on clinical findings, referred to a neurofibromatosis specialist for a thorough evaluation of musculoskeletal, cardiovascular, and neurologic systems, referred to an ophthalmologist for slit-lamp examination, and scheduled for a medical genetics consultation.
Melinda Liu, BA, is a medical student and Maura Holcomb, MD, is a dermatology resident at Baylor College of Medicine in Houston.
- Chernoff KA, Schaffer JV. Cutaneous and ocular manifestations of neurocutaneous syndromes. Clin Dermatol. 2016;34(2):183-204.
- Jouhilahti EM, Peltonen S, Heape AM, Peltonen J. The pathoetiology of neurofibromatosis 1. Am J Pathol. 2011;178(5):1932-1939.
- Shah KN. The diagnostic and clinical significance of café-au-lait macules. Pediatr Clin North Am. 2010;57(5):1131-1153.
- Tadini G, Brena M, Pezzani L, et al. Anemic nevus in neurofibromatosis type 1. Dermatology. 2013;226(2):115-118.
- Hernández-Martín A, García-Martínez FJ, Duat A, et al. Nevus anemicus: a distinctive cutaneous finding in neurofibromatosis type 1. Pediatr Dermatol. 2015;32(3):342-347.
- Ferner RE, Huson SM, Thomas N, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 2007;44(2):81-88.