Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited disorder that is estimated to occur in 1:2500 births and to have a prevalence of 1:2000 to 1:4000.1,2 It was first described in 1882 by Friedrich Daniel Von Recklinghausen, who identified patients and their relatives with signs of neuroectodermal abnormalities (café-au-lait macules [CALMs], axillary and inguinal freckling, and neurofibromas).
NF1 may begin insidiously in childhood and evolves as the patient ages. It is associated with intracranial, intraspinal, and intraorbital neoplasms, although other organs and tissues can also be involved.
The family physician might be the first one to recognize the signs of this condition during a well-child exam and is in a unique position to coordinate a multidisciplinary approach to care.
A mutated allele and early manifestations on the skin
NF1 has been attributed to genetic mosaicism and is classified as segmental, generalized, or (less frequently) gonadal. The disorder results from germline mutations in the NF1 tumor-suppressor gene on chromosome 17, known to codify the cytoplasmic protein called neurofibromin.3 The penetrance of NF1 is complete, which means that 100% of patients with the mutated allele will develop the disease.
Patients typically have symptoms by the third decade of life, although many will show signs of the disease in early childhood. CALMs are the earliest expression of NF1. They manifest in the first 2 years of life and are found in almost all affected patients. The lesions are well defined and measure 10 to 40 mm. They are typically light brown, although they may darken with sun exposure.
Histologically, the lesions will show macromelanosomes and high concentrations of melanin but do not represent an increased risk for malignancy.4 Not all isolated CALMs are a sign of NF1. While children younger than 29 months with 6 or more CALMs have a high risk for NF1 (80.4%; 95% confidence interval [CI], 74.6% to 86.2%), those who are older than 29 months with at least 1 atypical CALM or fewer than 6 CALMs have just a 0.9% (95% CI, 0% to 2.6%) risk for constitutional NF1.5
Freckles are also observed in 90% of patients with NF1; these tend to develop after the third year of life. The breast and trunk are the most commonly affected areas in adults. The pathophysiology is unknown, but this freckling is believed to be related to skin friction, high humidity, and ambient temperature.6
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